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T Cell Rewiring in Differentiation and Disease ¹

Sandeep Krishnan^*, Donna L. Farber and George C. Tsokos^2,*,

^* Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD 20910; Departments of Surgery and of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201; and Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814

	Introduction

Top Introduction Control points in the... Control points in distal... TCR signaling changes during... TCR rewiring in disease Concluding remarks References

 
The TCR-mediated signals leading to IL-2 production by T cell lines and naive T cells have been well characterized; however, the biochemical signaling mechanisms leading to disparate functions such as differentiation, effector cytokine production, death, and dysfunction due to immune pathologies are not known. In this review, we highlight recent studies that have identified specific alterations in proximal and distal TCR-coupled signaling and in the configuration of the TCR-signaling complex that occur as a result of T cell differentiation, and that have been associated with T cell dysfunctions in a number of diseases. We discuss how these specific alterations directly couple to disparate functions, and how these findings suggest that primary control of T cell functional outcomes can be traced to alterations in the activation state, configuration, and functional coupling of T cell-specific signaling intermediates.

T cell activation triggered via contact of the TCR with Ag/MHC is mediated by a series of biochemical events that transduce signals from the surface TCR to the nucleus, leading to activation of gene transcription for T cell proliferation and differentiation. TCR-coupled signaling leading to IL-2 production has been extensively characterized using the human T cell leukemia line Jurkat (1), which for over 20 years has been the model system of choice for dissecting the biochemical connections comprising TCR-coupled signal transduction. However, T cells can also mediate a variety of other functions depending on their activation/differentiation state and mode of activation, and T cells contribute to a variety of immune pathologies in autoimmune diseases. What is lacking in our knowledge of TCR-coupled signal transduction is a biochemical map of the routes that TCR-coupled signaling molecules follow to disparate functional destinations such as effector cytokine production, death, survival, anergy, memory, and T cell pathology.

TCR-coupled signaling comprises a series of phosphorylation events, kinase activation, and recruitment events, leading to the formation of molecular complexes that deliver sequential and converging biochemical messages from cytoplasm to nucleus. TCR ligation by Ag/MHC results in the phosphorylation of TCR-associated CD3 subunits, such as CD3 and CD3, by members of the src family kinase family, p56^lck and p59^fyn. Phosphorylated CD3 molecules subsequently recruit and activate the T cell-specific -associated protein-70 (ZAP-70)³ tyrosine kinase, which then phosphorylates the critical linker/adapter molecules linker for activation of T cells (LAT) and Src homology 2 domain-containing leukocyte protein-76 (SLP-76), which serve to form molecular complexes for coupling proximal phosphorylation to distal events (2). These distal events include activation and mobilization of GTP-binding proteins for cytoskeletal reorganization, activation of mitogen-activated protein kinases (MAPKs), and calcium flux, which together culminate in nuclear gene transcription (for reviews, see Refs. 3 and 4).

In this review, we discuss how specific stages in the TCR-coupled signaling cascade serve as control points for modulation of T cell function during activation and differentiation. We will present recent studies that have identified that changes in the expression, activation, and/or phosphorylation of signaling intermediates lead to rewiring of the TCR-coupled signaling pathway, with resultant functional consequences. Furthermore, we will present evidence that suggests that abnormal wiring of the TCR signaling machinery can contribute to disease pathology associated with chronic immune activation.

	Control points in the proximal TCR signaling complex

Top Introduction Control points in the... Control points in distal... TCR signaling changes during... TCR rewiring in disease Concluding remarks References

 
Analysis of the TCR structure has revealed that the signaling unit is a multimeric complex consisting of Ag/MHC binding - and -chains that associate with a group of invariant chains CD3, -, -, and - (reviewed in Ref. 5). These invariant chains stabilize TCR surface expression, and also act as signal initiators following TCR ligation by Ag/MHC by their immediate phosphorylation and recruitment of signaling molecules to the immunoreceptor tyrosine-based activation motifs (ITAMs) present on their cytoplasmic tails (6). The CD3, CD3, and CD3 subunits each bear single ITAMs, whereas CD3 bears three ITAMs. Two other proteins of the CD3 family, CD3 (derived by alternative splicing of the CD3 gene (7, 8) and FcR, originally found associated to the high affinity IgE receptor complex (9), bear two and one ITAM(s), respectively (10). The CD3, CD3, and FcR proteins share significant sequence homology, can stabilize surface TCR expression, and have been shown to functionally complement each other in vivo (10, 11, 12).

The TCR complex largely contains CD3-CD3-CD3 hetero- and homodimers (13); however, several studies have demonstrated that homologous subunits can replace the CD3 homodimer in the TCR complex. Although 90% of CD3 exists as homodimers in murine T cell clones, tumor cells, hybridomas, and normal splenic and thymic cells, CD3 can also form disulfide-linked heterodimers with the CD3 chain (14). Similarly, the murine CTLL cell line bears heterodimers of CD3 and FcR, and CD3 and FcR in the TCR complex (11). The FcR subunit has also been shown to be present in the TCR complex of specific nonconventional T cell types, such as human T cells (15), murine CD8⁺⁺ intraepithelial lymphocytes (16) and Ti ⁺NK1.1⁺ large granular lymphocytes (17).

The potential for differential phosphorylation and expression of ITAM-containing signaling subunits serves as initial control points for TCR-mediated signaling. For example, TCR stimulation induces two tyrosine-phosphorylated forms of the CD3 chain of 21 and 23 kDa (reviewed in Ref. 18), which trigger recruitment and activation of the Syk family kinases, ZAP-70 and Syk (19). Differential phosphorylation of CD3 leads to disparate functional outcomes, with a higher level of the 23-kDa form favoring ZAP-70 recruitment and phosphorylation and resultant T cell activation, whereas a preponderance of the 21-kDa form results in T cell anergy and lack of ZAP-70 phosphorylation (20, 21). In addition, the presence of CD3 or FcR on T cells can likewise affect Syk family kinase recruitment. Although CD3 recruits ZAP-70, FcR preferentially associates with Syk (22, 23). Although the precise functions of CD3 and FcR remain unclear, the differential binding affinities of tyrosine kinases to the three ITAMs of CD3 (24) suggest that lack of the first two ITAMs might serve as a mechanism for divergence of signaling for FcR. Consistent with this idea is the observation that FcR⁺ T cell hybridomas produce different levels of IL-2 than CD3⁺ counterparts (10).

	Control points in distal TCR signaling

Top Introduction Control points in the... Control points in distal... TCR signaling changes during... TCR rewiring in disease Concluding remarks References

 
The activation of Syk family kinases triggers two related signaling pathways that ultimately converge in transcription activation in the nucleus. One pathway involves phosphorylation-induced activation of phospholipase C-1 by Lck, ZAP-70, and Tec kinases in a process that is aided by the adapter proteins LAT and SLP-76 (reviewed in Ref. 25). Activated phospholipase C-1 splits membrane phosphatidylinositol 4,5-bisphosphate into inositol 1,4,5-triphosphate and diacylglycerol (26), leading to calcium flux, calmodulin/calcineurin-dependent activation (27), and translocation of NFAT for IL-2 production (28). The second pathway also involves the adapter proteins LAT and SLP-76, which interface with the linker/adapter Grb2-related adaptor downstream of Shc to couple ras/raf activation to MAPKs for IL-2 production (reviewed in Refs. 25 and 29).

Alterations in these pathways have been observed in response to TCR ligation leading to signaling divergence. On the linker/adapter level, diminished LAT phosphorylation was found to be triggered by antagonist peptide ligands, suggesting that alterations in the linker/adapter signaling may contribute to anergy induction (30, 31). Additional linker/adapter molecules have also been shown to be involved in regulation of signaling following initial activation. The adapter protein Nck was recently shown to be necessary for optimal T cell activation, and acts by binding to CD3 that is conformationally altered due to TCR-ligand binding (32). Another adapter protein, Clnk, gets up-regulated following treatment of cells with IL-2 and can induce the transcriptional activity of NFAT and AP-1 (33). Adapter molecules of the Cbl family, cCbl and Cbl-b, negatively regulate T cell activation by regulating the dynamics of TCR down-modulation following engagement with the Ag (34). These studies suggest that differential expression of adapter proteins may be a mechanism to achieve different functional outcomes.

Differential calcium responses and MAPK activation also determine whether a T cell undergoes activation or anergy following TCR ligation. Thus, anergy induced by antagonist peptide ligands was accompanied by sustained duration of induced calcium influxes (35, 36, 37). Similarly, anergy can be induced by maintaining sustained high levels of intracellular calcium, suggesting that altering calcium fluxes could be a mechanism for signaling control of T cell activation (38). Disparate patterns of MAPK phosphorylation are also observed in activated vs anergic T cells, with anergic cells exhibiting impairments in Ras activation and activation of the MAPKs, Erk1/2 and c-Jun N-terminal kinase (JNK) (39, 40).

Additional control of TCR-mediated signaling is triggered via costimulatory molecules that act to negatively regulate T cell activation, such as CTLA-4 and programmed death-1 gene. Although the signaling pathways coupled to these molecules are not fully elucidated, both have been shown to recruit phosphatases, such as protein phosphatase 2A (41) and Src homology 2-containing protein tyrosine phosphatase 2 (42), that presumably act to dephosphorylate key signaling intermediates, attenuating the cascade of activating signals from the TCR to the nucleus (43). A deficit in either of these molecules results in unchecked T cell proliferation and activation, or autoimmunity (44, 45, 46, 47), indicating that the integrity of pathways mediated by these negative regulators is critical for controlling T cell tolerance and preventing autoimmunity.

	TCR signaling changes during effector and memory T cell differentiation

Top Introduction Control points in the... Control points in distal... TCR signaling changes during... TCR rewiring in disease Concluding remarks References

 
The signaling control points described above have been identified during the initial activation of resting T cells leading to IL-2 production. The resultant activated cells then proliferate and differentiate to effector cells that produce effector cytokines such as IFN-, TNF-, IL-4, and or IL-10 for the coordination and regulation of Ag clearance. Although most of these effector cells die after Ag is cleared, a proportion of activated cells persist in a quiescent state as long-lived memory T cells, which mediate an enhanced and highly effective recall immune response upon Ag re-encounter. The mechanisms and TCR-coupled signaling changes underlying the distinct functions, life spans, and generation of effector and memory T cells are not known. Furthermore, it has been difficult to establish roles for specific signaling intermediates in effector and memory T cell differentiation, because mice genetically manipulated to lack key signaling intermediates, such as Lck (48), ZAP-70 (49), SLP-76 (50), LAT (51), and Erk (52), all exhibit profound defects in T cell development and lack peripheral T cells.

Our laboratories have closely examined TCR-coupled signaling pathways in naive, effector, and memory CD4 T cells from human and mice and have uncovered a number of striking differences in the biochemical pathways coupled to the TCR in these subsets. In general, TCR-mediated signaling in naive T cells, which primarily produce IL-2 when activated, resembles the general TCR signaling identified in T cell lines and clones (53, 54). By contrast, effector T cells are characterized by a profound amplification of signaling, manifested by an increase in tyrosine phosphorylation, which is further increased following TCR cross-linking (53, 54, 55). Memory T cells from humans and mice, in contrast to both naive and effector cells, are characterized by a dampening of signals through the TCR/CD3 complex, as manifested by a decrease in total tyrosine phosphorylation in the resting state and an absence of specific tyrosine-phosphorylated species following TCR/CD3 cross-linking (53, 54, 55, 56). These findings by our laboratories and others indicate that the distinct functions of naive, effector, and memory T cells are controlled, in part, by the specialized TCR-coupled signaling pathways present in these subsets.

We have further dissected the specific signaling alterations underlying the unique biochemical signatures of effector and memory CD4 T cells on proximal, linker/adapter, and distal levels (Table I). In mouse effector cells, earlier studies by Bachmann et al. (57) demonstrated increased Lck kinase activity in mouse effector CD8 T cells, consistent with our findings of enhanced tyrosine phosphorylation in effector T cells. However, other proximal events such as CD3 phosphorylation and ZAP-70 activation are not amplified in effector cells, and do not participate in effector cell-specific TCR signaling. For example, human effector T cells generated by anti-CD3 or antigenic stimuli, exhibit a dramatic decrease in expression of the CD3 protein, concomitant with a reduction in CD3 and TCR surface expression, and up-regulation of the FcR signaling subunit (55, 58). FcR in effector cells associates strongly with the TCR/CD3 complex after anti-CD3 stimulation, which excludes CD3 and ZAP-70, and contains FcR and the Syk tyrosine kinase, whose expression is likewise up-regulated in effector T cells (55, 58) (Fig. 1). On the linker/adapter level, we found striking increases in the phosphorylation of the linker/adapter molecules LAT and SLP-76, and increased association of phosphorylated proteins to the ubiquitous linker Grb2, which couples proximal events to ras activation, calcium flux, and MAPK activation (54). Distally, effector T cell signaling is also amplified with hyperphosphorylated MAPK activity and increased calcium flux (Ref. 54 and our unpublished data). Thus, TCR signaling in effector cells is initiated by an altered proximal TCR configuration concomitant with amplification of phosphorylation and signaling at the linker/adapter and distal levels (see Fig. 1). These downstream signaling amplifications are also found in effector CD8 T cells that phosphorylate LAT and MAPKs ERK, JNK, and p38 more efficiently than naive cells (59), and correlate to enhanced functional responses of effector cells including increased cytokine production (53, 55, 60) and response kinetics (61).

View larger version (67K): [in this window] [in a new window]   FIGURE 1. Rewiring of TCR in T cell differentiation and disease. The canonical TCR/CD3/CD3/ZAP-70 receptor complex in resting T cells from normal individuals (left panel) is replaced by TCR/CD3/FcR/Syk during T cell differentiation to become effector cells (middle panel). This in turn may be responsible for alterations in several biochemical pathways that are observed in effector cell signaling, such as increased calcium flux and ERK activity, and may mediate disparate patterns of cytokine production in these cell types as indicated. Close parallels can be drawn between effector cells of normal individuals (middle panel) and freshly isolated T cells from SLE patients (right panel), suggesting that the observed altered signaling pattern observed in SLE T cells may partially represent effector T cell phenotype. P, Phosphorylation status; +, increase in activity; -, decrease in activity.

Memory CD4 T cells exhibit a unique TCR-coupled signaling pattern, distinct from naive and effector cells. Whereas CD3 expression and phosphorylation are decreased in effector T cells, CD3 is highly expressed in memory T cells and is phosphorylated following TCR triggering of memory T cells (69, 70), although ZAP-70 is phosphorylated in mouse and human memory T cells to a lesser extent than in naive T cells (56, 70). Interestingly, the TCR signaling intermediates that are specifically amplified and hyperphosphorylated in effector cells are down-regulated and/or hypophosphorylated in memory T cells. For example, we found that mouse memory CD4 T cells are remarkably deficient in SLP-76 expression, although the related linker/adapter LAT is expressed in comparable levels in naive and memory T cells (54). The memory T cell-specific decrease in SLP-76 is consistent with the decreased calcium responses and IL-2 production previously identified in memory-phenotype CD4 T cells (71, 72, 73, 74), and also found in SLP-76-deficient Jurkat T cells (75). Whether a dampening of signals controlled by decreasing SLP-76 expression facilitates memory generation from effector cells, or whether memory cell signaling dampening results from their long-term maintenance and/or homeostasis remains to be established.

The role of the negative signaling regulators in different T cell stages is currently unclear. There is evidence that memory cells from both mice and humans contain small intracellular pools of CTLA-4 expression that may resist memory T cell activation in response to suboptimal stimulation (Refs.76 and 77 ; and V. G. Warke, D. L. Farber, G. C. Tsokos, unpublished observation). Programmed death-1 expression occurs in activated and not resting T cells (78) and may therefore play a role in controlling TCR signaling in effector and/or memory T cells.

Our findings of differential signaling in effector and memory T cells at the proximal and linker/adapter levels suggests that these signaling junctures serve as control points for regulation of T cell differentiation. We favor a model whereby alterations in the expression and/or activation and phosphorylation state of specific signaling intermediates during effector and/or memory generation, results in a rewiring of the TCR from the cytoplasm to the nucleus, through the establishment of distinct molecular complexes. The specific connections that result in turn, govern the unique functions and properties of these subsets. Further dissection of these novel pathways in effector and memory T cells will enable the specific targeting of these pathways in therapies to modulate effector and memory cell function in vivo in autoimmune, malignant, and infectious disease and in vaccine design.

	TCR rewiring in disease

Top Introduction Control points in the... Control points in distal... TCR signaling changes during... TCR rewiring in disease Concluding remarks References

 
Alterations in TCR-mediated signaling have been found in T cells isolated from individuals with a number of chronic diseases such as autoimmune diseases, chronic viral infections, and cancer. A reduction in the expression of CD3 chain has been shown to occur in T cells associated with viral infections such as HIV (79), EBV- and CMV-mediated infectious mononucleosis (80), cancer (81, 82, 83), and autoimmune diseases including rheumatoid arthritis (RA) (84) and systemic lupus erythematosus (SLE) (85). Although T cells in RA demonstrate CD3 loss as well (86), tumor-infiltrating lymphocytes (TILs) demonstrate an additional loss of CD3 (83). The involvement of chronic immune activation in the mediation of some of these effects is suggested by the effector phenotype of T cells in autoimmune diseases such as RA and SLE (87, 88).

The correlation of CD3 down-regulation with effector T cells generated from healthy individuals (55) raises the question of whether these signaling abnormalities simply indicate the presence of effector cells in these diseases marked by chronic immune activation. Our studies on peripheral T cells from patients with SLE indicate that these changes may, in part, derive from the presence of effector cells. Like effector cells, T cells from SLE patients exhibit decreases in CD3 expression (85, 89), FcR up-regulation and Syk recruitment to the TCR complex (90), increased and sustained distal signaling as measured by augmented calcium responses, and increased intracellular phosphorylation (85, 90). However, unlike healthy effector T cells, T cells from SLE patients display defects in the transcription of CD3 and the expression of activated Elf-1, which promotes CD3 transcription (85, 91) and reductions in IL-2 production (92, 93). However, effector cells have been shown to exhibit decreased IL-2 production at later times after activation (94), and activation-induced alterations in CD3 transcription have been demonstrated to occur in T cell lines (95), suggesting that SLE-specific T cell abnormalities may also be activation driven. The fact that these effector-like signaling alterations are found in freshly isolated peripheral blood T cells from SLE patients independent of the disease activity (85) suggests that there may be abnormal persistence of long-lived effector-like T cells in SLE. The presence of chronically activated effector cells in autoimmune diseases, in general, could also be due to impairments in negative regulation as suggested by findings that CTLA-4 polymorphisms are associated with a number of autoimmune diseases (96). Analysis of the biochemical mediators of positive and negative signaling in effector cells and SLE T cells will help resolve this issue.

TILs from a variety of sources also exhibit certain features of effector cells, yet similar to SLE T cells, show evidence of T cell impairments. Like effector cells, TILs from tumor-bearing mice exhibit replacement of CD3 by FcR in the TCR complex (83). Moreover, human TILs from multiple cancer cell types including renal cell carcinoma (81), melanoma (97), oral carcinoma (98), colorectal carcinoma (99), and ovarian carcinoma (100) exhibit strikingly reduced expression of CD3. However, mouse TILs also exhibit decreased calcium responses (83), suggesting functional impairments. Furthermore, the presence of T lymphocytes with low CD3 expression was found to correlate to low survival outcomes in patients with oral carcinoma (101, 102) and gastric carcinoma (103), and correlated with increased disease severity in colorectal carcinoma (104) and Hodgkin’s lymphoma (105), suggesting impaired immune effector function.

When taken together, T cells from different disease states exhibit similar proximal signaling alterations, yet altered function. These findings suggest two nonexclusive explanations for the origin of these signaling changes. First, distal signaling pathways and/or differential transcriptional activation may be found in disparate diseases. SLE T cells, for example, have been shown to up-regulate an IL-2 transcriptional repressor, cyclic adenosine 5'-monophosphate response element modulator, when compared with healthy T cells (106). Second, the observed signaling alterations may not necessarily govern T cell dysfunctions, but rather reflect the differentiation state on which the pathological influences within the disease environment, such as cytokines and an altered cellular composition, are exerted. Further dissections of signaling pathways used in T cells from disparate diseases will identify disease-specific signaling abnormalities and how they may arise.

	Concluding remarks

Top Introduction Control points in the... Control points in distal... TCR signaling changes during... TCR rewiring in disease Concluding remarks References

 
It appears that T cell differentiation carries a distinct biochemical signature that apparently precedes the functional phenotype. The work discussed herein clearly indicates T cell rewiring both at the proximal TCR receptor level and subsequent levels that determine the fate of the T cell. A theme that has arisen is that the T cells from SLE share many features with normal effector T cells including the down-regulation of the CD3 chain, the up-regulation of the FcR chain, the increased [Ca²⁺]_i, tyrosine phosphorylation response, and MAPK activation, yet exhibit alterations in the transcriptional machinery controlling cytokine production. The fact that certain biochemical steps characterize the behavior of the T cell raises enormous possibilities first for interventions to modify the rate of appearance of memory and effector T cells following exposure to Ag and for modulation of the T cells to limit disease pathology.

	Footnotes

 
¹ This work was supported by National Institutes of Health RO1 AI42092 (to D.L.F.), RO1 AI 42269, and RO1 AI49954 (to G.C.T.).

² Address correspondence and reprint requests to Dr. George C. Tsokos, Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD 20910-7500. E-mail address: gtsokos{at}usa.net

³ Abbreviations used in this paper: ZAP-70, -associated protein-70; LAT, linker for activation of T cells; SLP-76, Src homology 2 domain-containing leukocyte protein-76; MAPK, mitogen-activated protein kinase; ITAM, immunoreceptor tyrosine-based activation motif; JNK, c-Jun N-terminal kinase; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; TIL, tumor-infiltrating lymphocyte.

Received for publication May 14, 2003. Accepted for publication July 21, 2003.

	References

Top Introduction Control points in the... Control points in distal... TCR signaling changes during... TCR rewiring in disease Concluding remarks References

 

1. Gillis, S., M. Scheid, J. Watson. 1980. Biochemical and biologic characterization of lymphocyte regulatory molecules. III. The isolation and phenotypic characterization of interleukin-2 producing T cell lymphomas. J. Immunol. 125:2570.[Abstract]
2. Jordan, M. S., A. L. Singer, G. A. Koretzky. 2003. Adaptors as central mediators of signal transduction in immune cells. Nat. Immunol. 4:110.[Medline]
3. Clements, J. L., N. J. Boerth, J. R. Lee, G. A. Koretzky. 1999. Integration of T cell receptor-dependent signaling pathways by adapter proteins. Annu. Rev. Immunol. 17:89.[Medline]
4. Kane, L. P., J. Lin, A. Weiss. 2000. Signal transduction by the TCR for antigen. Curr. Opin. Immunol. 12:242.[Medline]
5. van Leeuwen, J. E., L. E. Samelson. 1999. T cell antigen-receptor signal transduction. Curr. Opin. Immunol. 11:242.[Medline]
6. Reth, M.. 1989. Antigen receptor tail clue. Nature 338:383.[Medline]
7. Ohno, H., T. Saito. 1990. CD3 and chains are produced by alternative splicing from a common gene. Int. Immunol. 2:1117.[Abstract/Free Full Text]
8. Clayton, L. K., L. D’Adamio, F. D. Howard, M. Sieh, R. E. Hussey, S. Koyasu, E. L. Reinherz. 1991. CD3 and CD3 are alternatively spliced products of a common genetic locus and are transcriptionally and/or post-transcriptionally regulated during T-cell development. Proc. Natl. Acad. Sci. USA 88:5202.[Abstract/Free Full Text]
9. Blank, U., C. Ra, L. Miller, K. White, H. Metzger, J. P. Kinet. 1989. Complete structure and expression in transfected cells of high affinity IgE receptor. Nature 337:187.[Medline]
10. Rodewald, H. R., A. R. Arulanandam, S. Koyasu, E. L. Reinherz. 1991. The high affinity Fc receptor subunit (FcRI) facilitates T cell receptor expression and antigen/major histocompatibility complex-driven signaling in the absence of CD3 and CD3. J. Biol. Chem. 266:15974.[Abstract/Free Full Text]
11. Orloff, D. G., C. S. Ra, S. J. Frank, R. D. Klausner, J. P. Kinet. 1990. Family of disulphide-linked dimers containing the and chains of the T-cell receptor and the chain of Fc receptors. Nature 347:189.[Medline]
12. Liu, C. P., W. J. Lin, M. Huang, J. W. Kappler, P. Marrack. 1997. Development and function of T cells in T cell antigen receptor/CD3 knockout mice reconstituted with FcRI. Proc. Natl. Acad. Sci. USA 94:616.[Abstract/Free Full Text]
13. Punt, J. A., J. L. Roberts, K. P. Kearse, A. Singer. 1994. Stoichiometry of the T cell antigen receptor (TCR) complex: each TCR/CD3 complex contains one TCR, one TCR, and two CD3 chains. J. Exp. Med. 180:587.[Abstract/Free Full Text]
14. Baniyash, M., P. Garcia-Morales, J. S. Bonifacino, L. E. Samelson, R. D. Klausner. 1988. Disulfide linkage of the and chains of the T cell receptor: possible identification of two structural classes of receptors. J. Biol. Chem. 263:9874.[Abstract/Free Full Text]
15. Hayes, S. M., P. E. Love. 2002. Distinct structure and signaling potential of the TCR complex. Immunity 16:827.[Medline]
16. Ohno, H., S. Ono, N. Hirayama, S. Shimada, T. Saito. 1994. Preferential usage of the Fc receptor chain in the T cell antigen receptor complex by / T cells localized in epithelia. J. Exp. Med. 179:365.[Abstract/Free Full Text]
17. Koyasu, S., L. D’Adamio, A. R. Arulanandam, S. Abraham, L. K. Clayton, E. L. Reinherz. 1992. T cell receptor complexes containing FcRI homodimers in lieu of CD3 and CD3 components: a novel isoform expressed on large granular lymphocytes. J. Exp. Med. 175:203.[Abstract/Free Full Text]
18. van Oers, N. S.. 1999. T cell receptor-mediated signs and signals governing T cell development. Semin. Immunol. 11:227.[Medline]
19. Chan, A. C., M. Iwashima, C. W. Turck, A. Weiss. 1992. ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR chain. Cell 71:649.[Medline]
20. Sloan-Lancaster, J., A. S. Shaw, J. B. Rothbard, P. M. Allen. 1994. Partial T cell signaling: altered phospho- and lack of zap70 recruitment in APL-induced T cell anergy. Cell 79:913.[Medline]
21. Madrenas, J., R. L. Wange, J. L. Wang, N. Isakov, L. E. Samelson, R. N. Germain. 1995. Phosphorylation without ZAP-70 activation induced by TCR antagonists or partial agonists. Science 267:515.[Abstract/Free Full Text]
22. Shiue, L., J. Green, O. M. Green, J. L. Karas, J. P. Morgenstern, M. K. Ram, M. K. Taylor, M. J. Zoller, L. D. Zydowsky, J. B. Bolen, et al 1995. Interaction of p72^syk with the and subunits of the high-affinity receptor for immunoglobulin E, FcRI. Mol. Cell. Biol. 15:272.[Abstract]
23. Shiue, L., M. J. Zoller, J. S. Brugge. 1995. Syk is activated by phosphotyrosine-containing peptides representing the tyrosine-based activation motifs of the high affinity receptor for IgE. J. Biol. Chem. 270:10498.[Abstract/Free Full Text]
24. Bu, J. Y., A. S. Shaw, A. C. Chan. 1995. Analysis of the interaction of ZAP-70 and syk protein-tyrosine kinases with the T-cell antigen receptor by plasmon resonance. Proc. Natl. Acad. Sci. USA 92:5106.[Abstract/Free Full Text]
25. Nel, A. E.. 2002. T-cell activation through the antigen receptor. Part 1. Signaling components, signaling pathways, and signal integration at the T-cell antigen receptor synapse. J. Allergy Clin. Immunol. 109:758.[Medline]
26. Park, D. J., H. W. Rho, S. G. Rhee. 1991. CD3 stimulation causes phosphorylation of phospholipase C-1 on serine and tyrosine residues in a human T-cell line. Proc. Natl. Acad. Sci. USA 88:5453.[Abstract/Free Full Text]
27. Hara, T., S. M. Fu, J. A. Hansen. 1985. Human T cell activation. II. A new activation pathway used by a major T cell population via a disulfide-bonded dimer of a 44 kilodalton polypeptide (9.3 antigen). J. Exp. Med. 161:1513.[Abstract/Free Full Text]
28. Straus, D. B., A. Weiss. 1992. Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor. Cell 70:585.[Medline]
29. Germain, R. N., I. Stefanova. 1999. The dynamics of T cell receptor signaling: complex orchestration and the key roles of tempo and cooperation. Annu. Rev. Immunol. 17:467.[Medline]
30. Leitenberg, D., K. Bottomly. 1999. Regulation of naive T cell differentiation by varying the potency of TCR signal transduction. Semin. Immunol. 11:283.[Medline]
31. Boutin, Y., D. Leitenberg, X. Tao, K. Bottomly. 1997. Distinct biochemical signals characterize agonist- and altered peptide ligand-induced differentiation of naive CD4⁺ T cells into Th1 and Th2 subsets. J. Immunol. 159:5802.[Abstract]
32. Gil, D., W. W. Schamel, M. Montoya, F. Sanchez-Madrid, B. Alarcon. 2002. Recruitment of Nck by CD3 reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. Cell 109:901.[Medline]
33. Cao, M. Y., D. Davidson, J. Yu, S. Latour, A. Veillette. 1999. Clnk, a novel SLP-76-related adaptor molecule expressed in cytokine-stimulated hemopoietic cells. J. Exp. Med. 190:1527.[Abstract/Free Full Text]
34. Naramura, M., I. K. Jang, H. Kole, F. Huang, D. Haines, H. Gu. 2002. c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. Nat. Immunol. 3:1192.[Medline]
35. Rabinowitz, J. D., C. Beeson, C. Wulfing, K. Tate, P. M. Allen, M. M. Davis, H. M. McConnell. 1996. Altered T cell receptor ligands trigger a subset of early T cell signals. Immunity 5:125.[Medline]
36. Sloan-Lancaster, J., T. H. Steinberg, P. M. Allen. 1996. Selective activation of the calcium signaling pathway by altered peptide ligands. J. Exp. Med. 184:1525.[Abstract/Free Full Text]
37. Gajewski, T. F., D. Qian, P. Fields, F. W. Fitch. 1994. Anergic T-lymphocyte clones have altered inositol phosphate, calcium, and tyrosine kinase signaling pathways. Proc. Natl. Acad. Sci. USA 91:38.[Abstract/Free Full Text]
38. Macian, F., F. Garcia-Cozar, S. H. Im, H. F. Horton, M. C. Byrne, A. Rao. 2002. Transcriptional mechanisms underlying lymphocyte tolerance. Cell 109:719.[Medline]
39. Fields, P. E., T. F. Gajewski, F. W. Fitch. 1996. Blocked Ras activation in anergic CD4⁺ T cells. Science 271:1276.[Abstract]
40. Li, W., C. D. Whaley, A. Mondino, D. L. Mueller. 1996. Blocked signal transduction to the ERK and JNK protein kinases in anergic CD4⁺ T cells. Science 271:1272.[Abstract]
41. Greenwald, R. J., Y. E. Latchman, A. H. Sharpe. 2002. Negative co-receptors on lymphocytes. Curr. Opin. Immunol. 14:391.[Medline]
42. Latchman, Y., C. R. Wood, T. Chernova, D. Chaudhary, M. Borde, I. Chernova, Y. Iwai, A. J. Long, J. A. Brown, R. Nunes, et al 2001. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2:261.[Medline]
43. Fraser, J. H., M. Rincon, K. D. McCoy, G. Le Gros. 1999. CTLA4 ligation attenuates AP-1, NFAT and NF-B activity in activated T cells. Eur. J. Immunol. 29:838.[Medline]
44. Tivol, E. A., F. Borriello, A. N. Schweitzer, W. P. Lynch, J. A. Bluestone, A. H. Sharpe. 1995. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:541.[Medline]
45. Waterhouse, P., J. M. Penninger, E. Timms, A. Wakeham, A. Shahinian, K. P. Lee, C. B. Thompson, H. Griesser, T. W. Mak. 1995. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270:985.[Abstract/Free Full Text]
46. Nishimura, H., M. Nose, H. Hiai, N. Minato, T. Honjo. 1999. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141.[Medline]
47. Nishimura, H., T. Okazaki, Y. Tanaka, K. Nakatani, M. Hara, A. Matsumori, S. Sasayama, A. Mizoguchi, H. Hiai, N. Minato, T. Honjo. 2001. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291:319.[Abstract/Free Full Text]
48. Molina, T. J., K. Kishihara, D. P. Siderovski, W. van Ewijk, A. Narendran, E. Timms, A. Wakeham, C. J. Paige, K. U. Hartmann, A. Veillette, et al 1992. Profound block in thymocyte development in mice lacking p56^lck. Nature 357:161.[Medline]
49. Negishi, I., N. Motoyama, K. Nakayama, K. Nakayama, S. Senju, S. Hatakeyama, Q. Zhang, A. C. Chan, D. Y. Loh. 1995. Essential role for ZAP-70 in both positive and negative selection of thymocytes. Nature 376:435.[Medline]
50. Clements, J. L., B. Yang, S. E. Ross-Barta, S. L. Eliason, R. F. Hrstka, R. A. Williamson, G. A. Koretzky. 1998. Requirement for the leukocyte-specific adapter protein SLP-76 for normal T cell development. Science 281:416.[Abstract/Free Full Text]
51. Zhang, W., C. L. Sommers, D. N. Burshtyn, C. C. Stebbins, J. B. DeJarnette, R. P. Trible, A. Grinberg, H. C. Tsay, H. M. Jacobs, C. M. Kessler, et al 1999. Essential role of LAT in T cell development. Immunity 10:323.[Medline]
52. Pages, G., S. Guerin, D. Grall, F. Bonino, A. Smith, F. Anjuere, P. Auberger, J. Pouyssegur. 1999. Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. Science 286:1374.[Abstract/Free Full Text]
53. Ahmadzadeh, M., S. F. Hussain, D. L. Farber. 1999. Effector CD4 T cells are biochemically distinct from the memory subset: evidence for long-term persistence of effectors in vivo. J. Immunol. 163:3053.[Abstract/Free Full Text]
54. Hussain, S. F., C. F. Anderson, D. L. Farber. 2002. Differential SLP-76 expression and TCR-mediated signaling in effector and memory CD4 T cells. J. Immunol. 168:1557.[Abstract/Free Full Text]
55. Krishnan, S., V. G. Warke, M. P. Nambiar, H. K. Wong, G. C. Tsokos, D. L. Farber. 2001. Generation and biochemical analysis of human effector CD4 T cells: alterations in tyrosine phosphorylation and loss of CD3 expression. Blood 97:3851.[Abstract/Free Full Text]
56. Hall, S. R., B. M. Heffernan, N. T. Thompson, W. C. Rowan. 1999. CD4⁺CD45RA⁺ and CD4⁺CD45RO⁺ T cells differ in their TCR-associated signaling responses. Eur. J. Immunol. 29:2098.[Medline]
57. Bachmann, M. F., A. Gallimore, S. Linkert, V. Cerundolo, A. Lanzavecchia, M. Kopf, A. Viola. 1999. Developmental regulation of Lck targeting to the CD8 coreceptor controls signaling in naive and memory T cells. J. Exp. Med. 189:1521.[Abstract/Free Full Text]
58. Krishnan, S., V. G. Warke, M. P. Nambiar, G. C. Tsokos, D. L. Farber. 2003. The FcR subunit and Syk kinase replace the CD3 chain and ZAP-70 kinase in the TCR signaling complex of human effector CD4 T cells. J. Immunol. 170:4189.[Abstract/Free Full Text]
59. Kersh, E. N., S. M. Kaech, T. M. Onami, M. Moran, E. J. Wherry, M. C. Miceli, R. Ahmed. 2003. TCR signal transduction in antigen-specific memory CD8 T cells. J. Immunol. 170:5455.
60. Ahmadzadeh, M., S. F. Hussain, D. L. Farber. 2001. Heterogeneity of the memory CD4 T cell response: persisting effectors and resting memory T cells. J. Immunol. 166:926.[Abstract/Free Full Text]
61. Iezzi, G., K. Karjalainen, A. Lanzavecchia. 1998. The duration of antigenic stimulation determines the fate of naive and effector T cells. Immunity 8:89.[Medline]
62. Nambiar, M. P., C. U. Fisher, A. Kumar, C. G. Tsokos, V. G. Warke, G. C. Tsokos. 2003. Forced expression of the Fc receptor -chain renders human T cells hyperresponsive to TCR/CD3 stimulation. J. Immunol. 170:2871.[Abstract/Free Full Text]
63. Oliver, J. M., D. L. Burg, B. S. Wilson, J. L. McLaughlin, R. L. Geahlen. 1994. Inhibition of mast cell FcR1-mediated signaling and effector function by the Syk-selective inhibitor, piceatannol. J. Biol. Chem. 269:29697.[Abstract/Free Full Text]
64. Dubey, C., M. Croft, S. L. Swain. 1996. Naive and effector CD4 T cells differ in their requirements for T cell receptor versus costimulatory signals. J. Immunol. 157:3280.[Abstract]
65. Yamashita, M., M. Kimura, M. Kubo, C. Shimizu, T. Tada, R. M. Perlmutter, T. Nakayama. 1999. T cell antigen receptor-mediated activation of the Ras/mitogen-activated protein kinase pathway controls interleukin 4 receptor function and type-2 helper T cell differentiation. Proc. Natl. Acad. Sci. USA 96:1024.[Abstract/Free Full Text]
66. Constant, S. L., C. Dong, D. D. Yang, M. Wysk, R. J. Davis, R. A. Flavell. 2000. JNK1 is required for T cell-mediated immunity against Leishmania major infection. J. Immunol. 165:2671.[Abstract/Free Full Text]
67. Yang, D. D., D. Conze, A. J. Whitmarsh, T. Barrett, R. J. Davis, M. Rincon, R. A. Flavell. 1998. Differentiation of CD4⁺ T cells to Th1 cells requires MAP kinase JNK2. Immunity 9:575.[Medline]
68. Rincon, M., H. Enslen, J. Raingeaud, M. Recht, T. Zapton, M. S. Su, L. A. Penix, R. J. Davis, R. A. Flavell. 1998. Interferon- expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway. EMBO J. 17:2817.[Medline]
69. Dorfman, J. R., I. Stefanova, K. Yasutomo, R. N. Germain. 2000. CD4⁺ T cell survival is not directly linked to self-MHC-induced TCR signaling. Nat. Immunol. 1:329.[Medline]
70. Farber, D. L., O. Acuto, K. Bottomly. 1997. Differential T cell receptor-mediated signaling in naive and memory CD4 T cells. Eur. J. Immunol. 27:2094.[Medline]
71. Miller, R. A.. 1989. Defective calcium signal generation in a T cell subset that accumulates in old mice. Ann. NY Acad. Sci. 568:271.[Abstract]
72. Philosophe, B., R. A. Miller. 1989. T lymphocyte heterogeneity in old and young mice: functional defects in T cells selected for poor calcium signal generation. Eur. J. Immunol. 19:695.[Medline]
73. Miller, R. A., B. Philosophe, I. Ginis, G. Weil, B. Jacobson. 1989. Defective control of cytoplasmic calcium concentration in T lymphocytes from old mice. J. Cell. Physiol. 138:175.[Medline]
74. Gorgas, G., E. R. Butch, K. L. Guan, R. A. Miller. 1997. Diminished activation of the MAP kinase pathway in CD3-stimulated T lymphocytes from old mice. Mech. Ageing Dev. 94:71.[Medline]
75. Yablonski, D., M. R. Kuhne, T. Kadlecek, A. Weiss. 1998. Uncoupling of nonreceptor tyrosine kinases from PLC-1 in an SLP-76-deficient T cell. Science 281:413.[Abstract/Free Full Text]
76. Metz, D. P., D. L. Farber, T. Taylor, K. Bottomly. 1998. Differential role of CTLA-4 in regulation of resting memory versus naive CD4 T cell activation. J. Immunol. 161:5855.[Abstract/Free Full Text]
77. Warke, V. G., S. Krishnan, M. P. Nambian, D. L. Farber, G. C. Tsokos, H. K. Wong. 2001. Identification of differentially expressed genes in human memory (CD45RO⁺) CD4⁺ T lymphocytes. Immunol. Invest. 30:87.[Medline]
78. Agata, Y., A. Kawasaki, H. Nishimura, Y. Ishida, T. Tsubata, H. Yagita, T. Honjo. 1996. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 8:765.[Abstract/Free Full Text]
79. Stefanova, I., M. W. Saville, C. Peters, F. R. Cleghorn, D. Schwartz, D. J. Venzon, K. J. Weinhold, N. Jack, C. Bartholomew, W. A. Blattner, et al 1996. HIV infection-induced posttranslational modification of T cell signaling molecules associated with disease progression. J. Clin. Invest. 98:1290.[Medline]
80. Trimble, L. A., L. W. Kam, R. S. Friedman, Z. Xu, J. Lieberman. 2000. CD3 and CD28 down-modulation on CD8 T cells during viral infection. Blood 96:1021.[Abstract/Free Full Text]
81. Finke, J. H., A. H. Zea, J. Stanley, D. L. Longo, H. Mizoguchi, R. R. Tubbs, R. H. Wiltrout, J. J. O’Shea, S. Kudoh, E. Klein, et al 1993. Loss of T-cell receptor chain and p56^lck in T-cells infiltrating human renal cell carcinoma. Cancer Res. 53:5613.[Abstract/Free Full Text]
82. Nakagomi, H., M. Petersson, I. Magnusson, C. Juhlin, M. Matsuda, H. Mellstedt, J. L. Taupin, E. Vivier, P. Anderson, R. Kiessling. 1993. Decreased expression of the signal-transducing chains in tumor-infiltrating T-cells and NK cells of patients with colorectal carcinoma. Cancer Res. 53:5610.[Abstract/Free Full Text]
83. Mizoguchi, H., J. J. O’Shea, D. L. Longo, C. M. Loeffler, D. W. McVicar, A. C. Ochoa. 1992. Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science 258:1795.[Abstract/Free Full Text]
84. Maurice, M. M., A. C. Lankester, A. C. Bezemer, M. F. Geertsma, P. P. Tak, F. C. Breedveld, R. A. van Lier, C. L. Verweij. 1997. Defective TCR-mediated signaling in synovial T cells in rheumatoid arthritis. J. Immunol. 159:2973.[Abstract]
85. Liossis, S. N., X. Z. Ding, G. J. Dennis, G. C. Tsokos. 1998. Altered pattern of TCR/CD3-mediated protein-tyrosyl phosphorylation in T cells from patients with systemic lupus erythematosus: deficient expression of the T cell receptor chain. J. Clin. Invest. 101:1448.[Medline]
86. Matsuda, M., A. K. Ulfgren, R. Lenkei, M. Petersson, A. C. Ochoa, S. Lindblad, P. Andersson, L. Klareskog, R. Kiessling. 1998. Decreased expression of signal-transducing CD3 chains in T cells from the joints and peripheral blood of rheumatoid arthritis patients. Scand. J. Immunol. 47:254.[Medline]
87. Duke, O., G. S. Panayi, G. Janossy, L. W. Poulter, N. Tidman. 1983. Analysis of T cell subsets in the peripheral blood and synovial fluid of patients with rheumatoid arthritis by means of monoclonal antibodies. Ann. Rheum. Dis. 42:357.[Abstract/Free Full Text]
88. Kammer, G. M., A. Perl, B. C. Richardson, G. C. Tsokos. 2002. Abnormal T cell signal transduction in systemic lupus erythematosus. Arthritis Rheum. 46:1139.[Medline]
89. Liossis, S. N., P. P. Sfikakis, G. C. Tsokos. 1998. Immune cell signaling aberrations in human lupus. Immunol. Res. 18:27.[Medline]
90. Enyedy, E. J., M. P. Nambiar, S. N. Liossis, G. Dennis, G. M. Kammer, G. C. Tsokos. 2001. Fc receptor type I chain replaces the deficient T cell receptor chain in T cells of patients with systemic lupus erythematosus. Arthritis Rheum. 44:1114.[Medline]
91. Juang, Y. T., K. Tenbrock, M. P. Nambiar, M. F. Gourley, G. C. Tsokos. 2002. Defective production of functional 98-kDa form of Elf-1 is responsible for the decreased expression of TCR -chain in patients with systemic lupus erythematosus. J. Immunol. 169:6048.[Abstract/Free Full Text]
92. Alcocer-Varela, J., D. Alarcon-Segovia. 1982. Decreased production of and response to interleukin-2 by cultured lymphocytes from patients with systemic lupus erythematosus. J. Clin. Invest. 69:1388.
93. Linker-Israeli, M., A. C. Bakke, R. C. Kitridou, S. Gendler, S. Gillis, D. A. Horwitz. 1983. Defective production of interleukin 1 and interleukin 2 in patients with systemic lupus erythematosus (SLE). J. Immunol. 130:2651.[Abstract]
94. Lederer, J. A., V. L. Perez, L. DesRoches, S. M. Kim, A. K. Abbas, A. H. Lichtman. 1996. Cytokine transcriptional events during helper T cell subset differentiation. J. Exp. Med. 184:397.[Abstract/Free Full Text]
95. Bronstein-Sitton, N., L. Wang, L. Cohen, M. Baniyash. 1999. Expression of the T cell antigen receptor chain following activation is controlled at distinct checkpoints: implications for cell surface receptor down-modulation and re-expression. J. Biol. Chem. 274:23659.[Abstract/Free Full Text]
96. Ueda, H., J. M. Howson, L. Esposito, J. Heward, H. Snook, G. Chamberlain, D. B. Rainbow, K. M. Hunter, A. N. Smith, G. Di Genova, et al 2003. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506.[Medline]
97. Dworacki, G., N. Meidenbauer, I. Kuss, T. K. Hoffmann, W. Gooding, M. Lotze, T. L. Whiteside. 2001. Decreased chain expression and apoptosis in CD3⁺ peripheral blood T lymphocytes of patients with melanoma. Clin. Cancer Res. 7:947s.
98. Reichert, T. E., L. Strauss, E. M. Wagner, W. Gooding, T. L. Whiteside. 2002. Signaling abnormalities, apoptosis, and reduced proliferation of circulating and tumor-infiltrating lymphocytes in patients with oral carcinoma. Clin. Cancer Res. 8:3137.[Abstract/Free Full Text]
99. Choi, S. H., E. J. Chung, D. Y. Whang, S. S. Lee, Y. S. Jang, C. W. Kim. 1998. Alteration of signal-transducing molecules in tumor-infiltrating lymphocytes and peripheral blood T lymphocytes from human colorectal carcinoma patients. Cancer Immunol. Immunother. 45:299.[Medline]
100. Lai, P., H. Rabinowich, P. A. Crowley-Nowick, M. C. Bell, G. Mantovani, T. L. Whiteside. 1996. Alterations in expression and function of signal-transducing proteins in tumor-associated T and natural killer cells in patients with ovarian carcinoma. Clin. Cancer Res. 2:161.[Abstract]
101. Reichert, T. E., R. Day, E. M. Wagner, T. L. Whiteside. 1998. Absent or low expression of the chain in T cells at the tumor site correlates with poor survival in patients with oral carcinoma. Cancer Res. 58:5344.[Abstract/Free Full Text]
102. Reichert, T. E., C. Scheuer, R. Day, W. Wagner, T. L. Whiteside. 2001. The number of intratumoral dendritic cells and -chain expression in T cells as prognostic and survival biomarkers in patients with oral carcinoma. Cancer 91:2136.[Medline]
103. Ishigami, S., S. Natsugoe, K. Tokuda, A. Nakajo, H. Higashi, H. Iwashige, K. Aridome, S. Hokita, T. Aikou. 2002. CD3- chain expression of intratumoral lymphocytes is closely related to survival in gastric carcinoma patients. Cancer 94:1437.[Medline]
104. Matsuda, M., M. Petersson, R. Lenkei, J. L. Taupin, I. Magnusson, H. Mellstedt, P. Anderson, R. Kiessling. 1995. Alterations in the signal-transducing molecules of T cells and NK cells in colorectal tumor-infiltrating, gut mucosal and peripheral lymphocytes: correlation with the stage of the disease. Int. J. Cancer 61:765.[Medline]
105. Frydecka, I., P. Kaczmarek, D. Bocko, A. Kosmaczewska, R. Morilla, D. Catovsky. 1999. Expression of signal-transducing chain in peripheral blood T cells and natural killer cells in patients with Hodgkin’s disease in different phases of the disease. Leuk. Lymphoma 35:545.[Medline]
106. Solomou, E. E., Y. T. Juang, M. F. Gourley, G. M. Kammer, G. C. Tsokos. 2001. Molecular basis of deficient IL-2 production in T cells from patients with systemic lupus erythematosus. J. Immunol. 166:4216.[Abstract/Free Full Text]

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