The JI
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     
 

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Renno, T.
Right arrow Articles by MacDonald, H. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Renno, T.
Right arrow Articles by MacDonald, H. R.
The Journal of Immunology, 1999, 162: 6312-6315.
Copyright © 1999 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Apoptosis of Superantigen-Activated T Cells Occurs Preferentially After a Discrete Number of Cell Divisions In Vivo1

Toufic Renno, Antoine Attinger, Sabrina Locatelli, Talitha Bakker, Sonia Vacheron and H. Robson MacDonald2

Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Staphylococcal enterotoxins are bacterial products that display superantigen activity in vitro as well as in vivo. For instance, staphylococcal enterotoxin B (SEB) polyclonally activates T cells that bear the Vß8 gene segment of the TCR. SEB-activated T cells undergo a burst of proliferation that is followed by apoptosis. Using an in vivo adaptation of a fluorescent cell division monitoring technique, we show here that SEB-activated T cells divide asynchronously, and that apoptosis of superantigen-activated T cells is preferentially restricted to cells which have undergone a discrete number of cell divisions. Collectively, our data suggest that superantigen-activated T cells are programmed to undergo a fixed number of cell divisions before undergoing apoptosis. A delayed death program may provide a mechanistic compromise between effector functions and homeostasis of activated T cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Following activation with staphylococcal enterotoxin B (SEB),3 T cells proliferate and eventually undergo apoptosis (1, 2, 3, 4, 5, 6, 7, 8). Surprisingly, it has been shown that the up-regulation of known apoptosis-mediating molecules such as Fas (reviewed in 9) or TNF receptor (reviewed in 10) on the surface of activated T cells does not confer immediate susceptibility to apoptosis (11, 12). One possible explanation of this apparent paradox is that activated T cells are programmed to acquire susceptibility to apoptosis only after a given number of cell divisions. Indeed, a precedent for such "cell division-associated" acquisition of specific function has been established for Ig isotype switch in activated B cells and for activation marker and cytokine expression in activated T cells (13, 14, 15, 16, 17). Linking apoptosis to cell division in activated T cells would allow expansion and effector function of the responding cells, while ensuring that these cells will ultimately undergo apoptosis, thus maintaining homeostasis. To address this possibility, we adapted a recently described cell division monitoring technique (18) that, when used in conjunction with cell surface phenotyping, allows the study of the relationship between the number of cell divisions and activation or death markers. Here, we show that SEB-reactive CD4+ T cells divide asynchronously in response to SEB in vivo, and that apoptosis of SEB-reactive T cells occurs preferentially after a discrete number of cell divisions.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Mice and treatment

We obtained 4- to 8-wk-old BALB/c mice from Harlan Olac (Bicester, U.K.). A total of 5 x 107 syngeneic splenocytes labeled with 5- (and 6-)carboxyfluorescein diacetate succinimidyl ester (CFSE) (Molecular Probes, Eugene, OR) (see below) were transferred i.v. into the tail vein. SEB (10 µg, purchased from Toxin Technology, Saratoga, FL) was injected into each of the hind footpads 1 day following cell transfer.

CFSE staining

Single-cell suspensions were made from spleens by homogenization into sterile high glucose DMEM (Life Technologies, Grand Island, NY). Debris was allowed to settle, and splenocytes were subsequently resuspended at 5 x 107/ml in PBS with no protein. CFSE was added to a final concentration of 5 µM, and the suspension was incubated at 37°C for 10 min. At the end of the incubation period, the cells were immediately washed three times in cold DMEM/10% FCS (Irvine Scientific, Santa Ana, CA).

Abs and flow cytometry

For three-color staining, the following mAbs were used: PE-labeled anti-CD4 (Boehringer Mannheim, Mannheim, Germany) and biotinylated anti-Vß8 (F23.1) (19) (revealed with streptavidin-tricolor (Caltag, San Fransisco, CA). For four-color staining, anti-Vß8-PE and anti-CD4-APC were purchased from PharMingen (San Diego, CA) and used in conjunction with annexin V staining (see below). Stained cells were analyzed on a FACScan or FACScalibur (Becton Dickinson, San Jose, CA).

Apoptosis assay

Annexin V (Nexins Research, Maastricht, The Netherlands) was used as described previously (20, 21, 22). Briefly, cells were washed in 100 µl of binding buffer and incubated in a 1/50 dilution of biotin-coupled annexin V solution for 20 min in the dark. Next, cells were washed, revealed with streptavidin tricolor (Caltag), and analyzed on the FACS.

Quantitation of SEB-reactive undivided cells

At 3 days after SEB administration, the percentage of cells in CFSE peaks was measured after electronically gating on CD4+ Vß8+ cells. To estimate the initial proportion of cells that gave rise to those in the different division peaks, we divided the percentage of cells in division peaks 1, 2, 3, and 4 by 2, 4, 8, and 16, respectively (because every two cells in a given division peak must have arisen from a single cell from the previous division peak). The corrected percentages thus obtained were used in the following formula: Percent undivided cells = U/(U + {Sigma}Dc), where U equals the percentage cells in the undivided CFSE peak and {Sigma}Dc equals the sum of the corrected percentages of cells in division peaks 1–4.

It should be noted that cell loss/apoptosis, although not accounted for by this analysis, would not significantly alter the outcome; it occurs mainly in division peak 4 (see Fig. 3Go), which only contributes a minor fraction of {Sigma}Dc.



View larger version (38K):
[in this window]
[in a new window]
  		FIGURE 3. Correlation of cell division with apoptosis in SEB-activated CD4+ Vß8+ T cells. Splenocytes were labeled with CFSE and transferred i.v. into syngeneic BALB/c recipients. At the indicated timepoints following injection with SEB, draining LN cells were analyzed for CFSE fluorescence (A), the percentage of total viable cells in each CFSE division peak (B), or the annexin V+ cells in each CFSE division peak (C) after gating on CD4+ Vß8+ cells. The data in A are a representative example, whereas B and C represent the mean ± SD of three individual mice per group.

 

   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
To investigate whether SEB-induced apoptosis of activated T cells is associated with the number of cell divisions in vivo, we used the dye CFSE, which covalently binds to cellular proteins and allows direct measurement by flow cytometry of cell divisions over several cell generations (18). We focused our analysis on the CD4 subset, because SEB-mediated clonal deletion has been shown to be more dramatic in CD4+ than in CD8+ T cells (8, 23, 24). CFSE-labeled spleen cells were injected i.v. into naive syngeneic mice. Typically, 2–3% CFSE+ T cells were detected in the lymphoid organs at 24 h after cell transfer (Fig. 1Go, inset), and this percentage remained stable over several days (data not shown). To ascertain that CFSE treatment did not compromise the ability of CD4+ T cells to respond normally to SEB, we measured the percentage of Vß8+ T cells within the CD4 subset in the draining lymph node (LN) in electronically gated CFSE-positive or -negative cells following injection of SEB. As can be seen in Fig. 1Go, the response to SEB in donor CFSE+ cells was virtually indistinguishable from the typical response of host CFSE- cells, confirming that neither T cell expansion nor deletion was affected by staining with CFSE.



View larger version (18K):
[in this window]
[in a new window]
  		FIGURE 1. Kinetics of response to SEB in host (CFSE-) and donor (CFSE+) T cells. Splenocytes were labeled with CFSE and transferred i.v. into syngeneic BALB/c recipients. At the indicated timepoints following injection with SEB, the percentage of Vß8+ cells was quantitated in the draining LN after electronically gating on CD4+CFSE+ or CD4+CFSE- cells. Inset: FACS histogram showing CFSE+ donor cells (right peak) and CFSE- host cells (left peak) in the absence of SEB stimulation.

 
We subsequently confirmed that CFSE can be used to monitor the specific cell division induced by SEB in vivo. In the representative example shown in Fig. 2Go, five distinct peaks of CFSE fluorescence intensity (each differing by a factor of two from adjoining peaks) were detected among donor-derived CD4+ Vß8+ cells in the draining LN 3 days after SEB injection. The brightest peak corresponds to undivided cells, whereas the four remaining peaks identify cells that have undergone 1, 2, 3, and 4 divisions, respectively. As expected, very few CD4+ Vß8- cells divided in response to SEB during this time period, resulting in a dominant CFSE peak that corresponded to undivided cells (Fig. 2Go). Kinetic analysis of CFSE fluorescence among CD4+ Vß8+ cells following SEB injection indicated a progressive increase in the number of cell divisions between 36 and 72 h, when a fourth (and to a lesser extent fifth) division peak was observed (Fig. 3GoA). No additional cell division was detected between 72 and 96 h. Quantitation of the proportion of CD4+ Vß8+ cells in each CFSE division peak (Fig. 3GoB) confirmed that SEB-induced proliferation progressed from 36 to 72 h and subsequently ceased. Several points can be made from these data. First, there is a clearly defined population of undivided CD4+ Vß8+ cells that is detectable even at the latest timepoints. Indeed, we calculate (see Materials and Methods for details) that the proportion of undivided cells in the draining LN at 3–4 days after challenge with SEB corresponds to 35–45% (n = 7) of the initial CD4+ Vß8+ population, confirming our previous estimates obtained with continuous 5-bromodeoxyuridine labeling (6). The presence of such a substantial fraction of undivided cells expressing a SEB-specific Vß domain cannot be attributed simply to a failure to contact SEB, because virtually all (>95%) Vß8+ T cells underwent CD62 ligand down-regulation and CD69 up-regulation following SEB injection (Ref. 25 and our unpublished observations). Whatever the explanation, it is likely that these undivided cells represent the so-called "anergic" population that remains 7–10 days after SEB challenge, because our previous studies have demonstrated that virtually all dividing cells eventually die after SEB stimulation (6).



View larger version (37K):
[in this window]
[in a new window]
  		FIGURE 2. Example of CFSE fluorescence in T cells following SEB injection in vivo. Splenocytes were labeled with CFSE and transferred i.v. into syngeneic BALB/c recipients. At 3 days following injection with SEB, CFSE fluorescence in draining LN cells was analyzed after gating on CD4+ Vß8+ or CD4+ Vß8- cells. Boxed numbers refer to respective division peaks; "U" refers to undivided cells; "H" refers to host-derived, CFSE-unlabeled cells. To increase the proportion of CFSE+ cells in the analysis, most cells in peak "H" were electronically eliminated using FL-1 threshold. The mean fluorescence values for the five CFSE peaks from right to left are 1036, 441, 236, 125, and 63, respectively.

 
A second important point arising from the CFSE distribution patterns in Figs. 2Go and 3Go is that CD4+ Vß8+ cells are widely distributed among the division peaks at all timepoints after SEB injection. This in turn implies that there is considerable heterogeneity at the single-cell level in the SEB response in vivo. This heterogeneity in cell division among SEB-reactive cells could arise in any of the following ways: 1) asynchrony in contacting SEB and initiating the response, 2) asynchrony in reaching the first mitosis, 3) variations in cell cycle time among dividing cells, 4) variations in cell loss/apoptosis during different division cycles. Because cell cycle parameters are difficult to assess in asynchronous and nonhomogeneous cell populations, we decided to concentrate our attention on apoptosis.

Annexin V is a ligand of phosphatidylserine that, in living cells, is stringently located in the membrane leaflets that face the cytosol. During the early stages of apoptosis, the cell membrane loses asymmetry and phosphatidylserine becomes exposed on the cell surface, where it functions as a tag to signal phagocytes, which then clear the dying cell (20, 21, 22). To directly assess the relationship between apoptosis and cell division in SEB-activated T cells, we evaluated annexin V binding to the surface of dividing CD4+ Vß8+ T cells in the draining LN at various times. For these experiments, activated T cells were incubated in vitro (1 h at 37°C) as described previously to allow apoptosis to occur (6, 26). As shown in Fig. 3GoC, there was a relatively low frequency of apoptotic cells associated with the first three rounds of division irrespective of the time after SEB injection. In contrast, there was a striking increase in the number of apoptotic cells in CFSE peaks corresponding to CD4+ Vß8+ cells that had divided four or five times. Importantly, the association of apoptosis with division peaks 4 and 5 was observed independently of the time after SEB injection, demonstrating that the number of cell divisions (rather than kinetic parameters) was responsible for this phenomenon. It should be noted that the actual number of cell divisions correlating with the induction of apoptosis was constant within a given experiment but varied slightly (usually by no more than one cycle) from one experiment to another.

In conclusion, our data suggest that upon activation by superantigens, T cells are programmed to undergo a fixed number of cell divisions before undergoing apoptosis. The molecular mechanism underlying such a delayed death program in activated T cells remains to be established. One possibility would be that some long-lived inhibitor of apoptosis is induced early after activation and gradually diluted out during subsequent cell divisions, leading eventually to apoptosis. Alternatively, a critical death effector molecule may be induced (or up-regulated) specifically after a fixed number of cell divisions. Finally, it is possible that apoptosis in this model is not causally linked to cell division but rather to some other parameter (such as activation state) that correlates with division status. Whatever the mechanism, it is tempting to speculate that apoptosis is regulated in this way so as to allow T cells to expand and perform their effector functions, while at the same time ensuring homeostasis.


   Footnotes
 
1 T.R. is supported by a Centennial Fellowship from the Medical Research Council of Canada and by the Ciba Jubilee Foundation. H.R.M. and A.A. are supported in part by a grant (RG-544/95) from the Human Frontier Science Program. Back

2 Address correspondence and reprint requests to Dr. H. Robson MacDonald, Ludwig Institute for Cancer Research, Chemin des Boveresses 155, 1066 Epalinges, Switzerland. E-mail address: Back

3 Abbreviations used in this paper: SEB, staphylococcal enterotoxin B; CFSE, 5- (and 6-)carboxyfluorescein diacetate succinimidyl ester; LN, lymph node. Back

Received for publication December 28, 1998. Accepted for publication March 29, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

  1. Webb, S., C. Morris, J. Sprent. 1990. Extrathymic tolerance of mature T cells: clonal elimination as a consequence of immunity. Cell 63:1249.[Medline]
  2. MacDonald, H. R., S. Baschieri, R Lees. 1991. Clonal expansion precedes anergy and death of Vß8+ peripheral T cells responding to staphylococcal enterotoxin B in vivo. Eur. J. Immunol. 21:1963.[Medline]
  3. Wahl, C., T. Miethke, K. Heeg, H. Wagner. 1993. Clonal deletion as a direct consequence of an in vivo T cell response to bacterial superantigen. Eur. J. Immunol. 23:1197.[Medline]
  4. Kyburz, D., P. Aichele, D. E. Speiser, H. Hengartner, R. M. Zinkernagel, H. Pircher. 1993. T cell immunity after a viral infection versus T cell tolerance induced by soluble viral peptides. Eur. J. Immunol. 23:1956.[Medline]
  5. Huang, L., G. Soldevila, M. Leeker, R. Flavell, I. N. Crispe. 1995. The liver eliminates T cells undergoing antigen-triggered apoptosis in vivo. Immunity 1:741.
  6. Renno, T., M. Hahne, H. R. MacDonald. 1995. Proliferation is a prerequisite for bacterial superantigen-induced T cell apoptosis in vivo. J. Exp. Med. 181:2283.[Abstract/Free Full Text]
  7. Kawabe, Y., A. Ochi. 1991. Programmed cell death and extrathymic reduction of Vß8+ CD4+ T cells in mice tolerant to Staphylococcus aureus enterotoxin B. Nature 349:245.[Medline]
  8. Gonzalo, J. A., C. Martinez, T. A. Springer, J. C. Gutierrez-Ramos. 1995. ICAM-1 is required for T cell proliferation but not for anergy or apoptosis induced by Staphylococcus aureus enterotoxin B in vivo. Int. Immunol. 7:1691.
  9. Nagata, S.. 1994. Fas and Fas ligand: a death factor and its receptor. Adv. Immunol. 57:129.[Medline]
  10. Tartaglia, L. A., D. V. Goeddel. 1992. Two TNF receptors. Immunol. Today 13:151.[Medline]
  11. Boussiotis, V. A., B. J. Lee, G. J. Freeman, J. G. Gribben, L. M. Nadler. 1997. Induction of T cell clonal anergy results in resistance, whereas CD28-mediated costimulation primes for susceptibility to Fas- and Bax-mediated programmed cell death. J. Immunol. 159:3156.[Abstract]
  12. Hornung, F., L. Zheng, M. J. Lenardo. 1997. Maintenance of clonotype specificity in CD95/Apo-1/Fas-mediated apoptosis of mature T lymphocytes. J. Immunol. 159:3816.[Abstract]
  13. Hodgkin, P. D., J. H. Lee, A. B. Lyons. 1996. B cell differentiation and isotype switching is related to division cycle number. J. Exp. Med. 184:277.[Abstract/Free Full Text]
  14. Gett, A. V., P. D. Hodgkin. 1998. Cell division regulates the T cell cytokine repertoire, revealing a mechanism underlying immune class regulation. Proc. Natl. Acad. Sci. USA 95:9488.[Abstract/Free Full Text]
  15. Lee, W. T., W. J. Pelletier. 1998. Visualizing memory phenotype development after in vitro stimulation of CD4+ T cells. Cell. Immunol. 188:1.[Medline]
  16. Oehen, S., K. Brduscha-Rhiem. 1998. Differentiation of naive CTL to effector and memory CTL: correlation of effector function with phenotype and cell division. J. Immunol. 161:5338.[Abstract/Free Full Text]
  17. Bird, J. J., D. R. Brown, A. C. Mullen, N. H. Moskowitz, M. A. Mahowald, J. R. Sider, T. F. Gajewski, C. R. Wang, S. L. Reiner. 1998. Helper T cell differentiation is controlled by the cell cycle. Immunity 9:229.[Medline]
  18. Lyons, A. B., C. R. Parish. 1994. Determination of lymphocyte division by flow cytometry. J. Immunol. Methods 171:131.[Medline]
  19. Staerz, U. D., H. Rammensee, J. Bendetto, M. Bevan. 1985. Characterization of a murine monoclonal antibody specific for an allotypic determinant on T cell antigen receptor. J. Immunol. 134:3994.[Abstract]
  20. Martin, S. J., C. P. M. Reutelinsperger, A. J. Mcgahon, J. A. Rader, R. C. A. A. van Schie, D. M. LaFace, D. R. Green. 1995. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of bcl-2 and abl. J. Exp. Med. 182:1545.[Abstract/Free Full Text]
  21. Verhoven, B., R. A. Schlegel, P. Williamson. 1995. Mechanisms of phosphatidylserine exposure, a phagocyte recognition signal, on apoptotic T lymphocytes. J. Exp. Med. 182:1597.[Abstract/Free Full Text]
  22. Thiagarajan, P., J. F. Tait. 1990. Binding of annexin V/placental anticoagulant protein I to platelets: evidence for phosphatidylserine exposure in the procoagulant response of activated platelets. J. Biol. Chem. 256:17420.
  23. MacDonald, H. R., R. K. Lees, S. Baschieri, T. Herrmann, A. T. Lussow. 1993. Peripheral T-cell reactivity to bacterial superantigens in vivo: the response/anergy paradox. Immunol. Rev. 133:105.[Medline]
  24. Scott, D. E., W. J. Kisch, A. D. Steinberg. 1993. Studies of T cell deletion and T cell anergy following in vivo administration of SEB to normal and lupus-prone mice. J. Immunol. 150:664.[Abstract]
  25. Miethke, T., C. Wahl, B. Holzmann, K. Heeg, H. Wagner. 1993. Bacterial superantigens induce rapid T cell receptor Vß-selective down-regulation of L-selectin (gp90Mel-14) in vivo. J. Immunol. 151:6777.[Abstract]
  26. Renno, T., M. Hahne, J. Tschopp, H. R. MacDonald. 1996. Peripheral T cells undergoing superantigen-induced apoptosis in vivo express B220 and upregulate Fas and Fas ligand. J. Exp. Med. 183:431.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 BloodHome page
C. Calissano, R. N. Damle, G. Hayes, E. J. Murphy, M. K. Hellerstein, C. Moreno, C. Sison, M. S. Kaufman, J. E. Kolitz, S. L. Allen, et al.
In vivo intraclonal and interclonal kinetic heterogeneity in B-cell chronic lymphocytic leukemia
Blood, November 26, 2009; 114(23): 4832 - 4842.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
J. L. DeHart, A. Bosque, R. S. Harris, and V. Planelles
Human Immunodeficiency Virus Type 1 Vif Induces Cell Cycle Delay via Recruitment of the Same E3 Ubiquitin Ligase Complex That Targets APOBEC3 Proteins for Degradation
J. Virol., September 15, 2008; 82(18): 9265 - 9272.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
A. Bosque, J. I. Aguilo, M. del Rey, E. Paz-Artal, L. M. Allende, J. Naval, and A. Anel
Cell cycle regulation by FasL and Apo2L/TRAIL in human T-cell blasts. Implications for autoimmune lymphoproliferative syndromes
J. Leukoc. Biol., August 1, 2008; 84(2): 488 - 498.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
V. V. Ganusov, D. Milutinovic, and R. J. De Boer
IL-2 Regulates Expansion of CD4+ T Cell Populations by Affecting Cell Death: Insights from Modeling CFSE Data
J. Immunol., July 15, 2007; 179(2): 950 - 957.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
K. S. Seo, S. U. Lee, Y. H. Park, W. C. Davis, L. K. Fox, and G. A. Bohach
Long-Term Staphylococcal Enterotoxin C1 Exposure Induces Soluble Factor-Mediated Immunosuppression by Bovine CD4+ and CD8+ T Cells
Infect. Immun., January 1, 2007; 75(1): 260 - 269.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
R. Plaza, J. L. Rodriguez-Sanchez, and C. Juarez
Staphylococcal Enterotoxin B In Vivo Modulates both Gamma Interferon Receptor Expression and Ligand-Induced Activation of Signal Transducer and Activator of Transcription 1 in T Cells
Infect. Immun., January 1, 2007; 75(1): 306 - 313.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
J. Unsinger, J. M. Herndon, C. G. Davis, J. T. Muenzer, R. S. Hotchkiss, and T. A. Ferguson
The Role of TCR Engagement and Activation-Induced Cell Death in Sepsis-Induced T Cell Apoptosis
J. Immunol., December 1, 2006; 177(11): 7968 - 7973.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
D. Ding, H. Mehta, W. J. McCune, and M. J. Kaplan
Aberrant Phenotype and Function of Myeloid Dendritic Cells in Systemic Lupus Erythematosus
J. Immunol., November 1, 2006; 177(9): 5878 - 5889.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
P. K. A. Mongini, J. K. Inman, H. Han, R. J. Fattah, S. B. Abramson, and M. Attur
APRIL and BAFF Promote Increased Viability of Replicating Human B2 Cells via Mechanism Involving Cyclooxygenase 2.
J. Immunol., June 1, 2006; 176(11): 6736 - 6751.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
A. P. Uldrich, S. P. Berzins, M. A. Malin, P. Bouillet, A. Strasser, M. J. Smyth, R. L. Boyd, and D. I. Godfrey
Antigen challenge inhibits thymic emigration.
J. Immunol., April 15, 2006; 176(8): 4553 - 4561.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
C. S. Goodyear, F. Sugiyama, and G. J. Silverman
Temporal and Dose-Dependent Relationships between In Vivo B Cell Receptor-Targeted Proliferation and Deletion-Induced by a Microbial B Cell Toxin
J. Immunol., February 15, 2006; 176(4): 2262 - 2271.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
P. K. A. Mongini, J. K. Inman, H. Han, S. L. Kalled, R. J. Fattah, and S. McCormick
Innate Immunity and Human B Cell Clonal Expansion: Effects on the Recirculating B2 Subpopulation
J. Immunol., November 1, 2005; 175(9): 6143 - 6154.
[Abstract] [Full Text] [PDF]

Home page
 Br J OphthalmolHome page
Y Jie, Z Pan, Y Chen, Y Wei, W Zhang, Y Wu, H Peng, and L Xu
Non-specific tolerance induced by staphylococcal enterotoxin B in treating high risk corneal transplantation in rats
Br J Ophthalmol, March 1, 2005; 89(3): 364 - 368.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
I.V. Kovtun, A.R. Thornhill, and C.T. McMurray
Somatic deletion events occur during early embryonic development and modify the extent of CAG expansion in subsequent generations
Hum. Mol. Genet., December 15, 2004; 13(24): 3057 - 3068.
[Abstract] [Full Text] [PDF]

Home page
 CVIHome page
T. W. McCloskey, V. Haridas, L. Pontrelli, and S. Pahwa
Response to Superantigen Stimulation in Peripheral Blood Mononuclear Cells from Children Perinatally Infected with Human Immunodeficiency Virus and Receiving Highly Active Antiretroviral Therapy
Clin. Vaccine Immunol., September 1, 2004; 11(5): 957 - 962.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
R. Mallone, S. A. Kochik, E. M. Laughlin, V. H. Gersuk, H. Reijonen, W. W. Kwok, and G. T. Nepom
Differential Recognition and Activation Thresholds in Human Autoreactive GAD-Specific T-Cells
Diabetes, April 1, 2004; 53(4): 971 - 977.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
B. R. Lawson, R. Baccala, J. Song, M. Croft, D. H. Kono, and A. N. Theofilopoulos
Deficiency of the Cyclin Kinase Inhibitor p21(WAF-1/CIP-1) Promotes Apoptosis of Activated/Memory T Cells and Inhibits Spontaneous Systemic Autoimmunity
J. Exp. Med., February 17, 2004; 199(4): 547 - 557.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
E. K. Deenick, A. V. Gett, and P. D. Hodgkin
Stochastic Model of T Cell Proliferation: A Calculus Revealing IL-2 Regulation of Precursor Frequencies, Cell Cycle Time, and Survival
J. Immunol., May 15, 2003; 170(10): 4963 - 4972.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
M. Maksimow, M. Santanen, S. Jalkanen, and A. Hanninen
Responding naive T cells differ in their sensitivity to Fas engagement: early death of many T cells is compensated by costimulation of surviving T cells
Blood, May 15, 2003; 101(10): 4022 - 4028.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
C. S. Goodyear and G. J. Silverman
Death by a B Cell Superantigen: In Vivo VH-targeted Apoptotic Supraclonal B Cell Deletion by a Staphylococcal Toxin
J. Exp. Med., May 5, 2003; 197(9): 1125 - 1139.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
J. Gonzalez, A. Orlofsky, and M. B. Prystowsky
A1 is a growth-permissive antiapoptotic factor mediating postactivation survival in T cells
Blood, April 1, 2003; 101(7): 2679 - 2685.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
R. Suresh, M. Vig, S. Bhatia, E. P. B. Goodspeed, B. John, U. Kandpal, S. Srivastava, A. George, R. Sen, V. Bal, et al.
Pentoxifylline Functions As an Adjuvant In Vivo to Enhance T Cell Immune Responses by Inhibiting Activation-Induced Death
J. Immunol., October 15, 2002; 169(8): 4262 - 4272.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
B. R. Lawson, D. H. Kono, and A. N. Theofilopoulos
Deletion of p21 (WAF-1/Cip1) Does Not Induce Systemic Autoimmunity in Female BXSB Mice
J. Immunol., June 1, 2002; 168(11): 5928 - 5932.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
J. Wipasa, H. Xu, A. Stowers, and M. F. Good
Apoptotic Deletion of Th Cells Specific for the 19-kDa Carboxyl-Terminal Fragment of Merozoite Surface Protein 1 During Malaria Infection
J. Immunol., October 1, 2001; 167(7): 3903 - 3909.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M.-L. Santiago-Raber, B. R. Lawson, W. Dummer, M. Barnhouse, S. Koundouris, C. B. Wilson, D. H. Kono, and A. N. Theofilopoulos
Role of Cyclin Kinase Inhibitor p21 in Systemic Autoimmunity
J. Immunol., October 1, 2001; 167(7): 4067 - 4074.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
L. C. Gavrilescu and E. Y. Denkers
IFN-{{gamma}} Overproduction and High Level Apoptosis Are Associated with High but Not Low Virulence Toxoplasma gondii Infection
J. Immunol., July 15, 2001; 167(2): 902 - 909.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
S. Chavan, S. Kodoth, R. Pahwa, and S. Pahwa
The HIV protease inhibitor Indinavir inhibits cell-cycle progression in vitro in lymphocytes of HIV-infected and uninfected individuals
Blood, July 15, 2001; 98(2): 383 - 389.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
P. M. Lavoie, H. McGrath, N. H. Shoukry, P.-A. Cazenave, R.-P. Sekaly, and J. Thibodeau
Quantitative Relationship Between MHC Class II-Superantigen Complexes and the Balance of T Cell Activation Versus Death
J. Immunol., June 15, 2001; 166(12): 7229 - 7237.
[Abstract] [Full Text] [PDF]

Home page
 Int ImmunolHome page
K. Izeradjene, J.-P. Revillard, and L. Genestier
Inhibition of thymidine synthesis by folate analogues induces a Fas-Fas ligand-independent deletion of superantigen-reactive peripheral T cells
Int. Immunol., January 1, 2001; 13(1): 85 - 93.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
H. Noorchashm, D. J. Moore, L. E. Noto, N. Noorchashm, A. J. Reed, A. L. Reed, H. K. Song, R. Mozaffari, A. M. Jevnikar, C. F. Barker, et al.
Impaired CD4 T Cell Activation Due to Reliance Upon B Cell-Mediated Costimulation in Nonobese Diabetic (NOD) Mice
J. Immunol., October 15, 2000; 165(8): 4685 - 4696.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
A. Attinger, H. Acha-Orbea, and H. R. MacDonald
Cutting Edge: Cell Autonomous Rather Than Environmental Factors Control Bacterial Superantigen-Induced T Cell Anergy In Vivo
J. Immunol., August 1, 2000; 165(3): 1171 - 1174.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
D. Rosen, J.-H. Li, S. Keidar, I. Markon, R. Orda, and G. Berke
Tumor Immunity in Perforin-Deficient Mice: A Role for CD95 (Fas/APO-1)
J. Immunol., March 15, 2000; 164(6): 3229 - 3235.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Renno, T.
Right arrow Articles by MacDonald, H. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Renno, T.
Right arrow Articles by MacDonald, H. R.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS