| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Departments of
*
Laboratory Medicine and Pathology,
Pediatrics,
Medicine, and
Microbiology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
T cell recognition of specific self peptide/MHC ligands is important for optimal homeostatic expansion, and cells undergoing this process become phenotypically and functionally indistinguishable from memory T cells (5, 6, 9). Together, these data suggest that homeostatic expansion involves a TCR signal that induces functional differentiation. As is well established, T proliferative responses toward conventional foreign peptide/MHC ligands require a second signal, referred to as costimulation, to avoid T cell anergy or death. Costimulation is mediated by a variety of cell surface molecules of which CD28/B7 and CD40L/CD40 interactions are the best characterized (reviewed in Refs. 10 and 11), although several other molecules may synergize with or even substitute for these classic costimulators (reviewed in Refs. 12, 13, 14). Prominent among these is the 4-1BB/4-1BBL interaction that can both augment and substitute for CD28/B7 interactions in both CD4 and CD8 T cell responses (12, 15, 16, 17, 18). However, the role of costimulation in homeostatic expansion has not been well defined. Unpublished data from two groups suggest that CD28 is not essential for homeostatic expansion (6, 8), a result that might reflect true independence of homeostatic expansion from costimulation, or could instead point to functional redundancy among costimulatory pathways. In this study, we show that homeostatic expansion does not require CD28 on the T cell, nor does it require CD40 or 4-1BBL expression on host APCs. This was true even when combinations of costimulator deficiencies were studied (i.e., CD28-/- T cells transferred into CD40-/- or 4-1BBL-/- hosts). Indeed, in contrast to the critical role of CD28 in responses to foreign Ags, we show that CD28-deficient cells proliferate as well (or even slightly better) than wild-type cells during homeostatic expansion of DO11.10 TCR transgenic T cells. This unexpected result did not appear to correlate with the presence or absence of the CD4+CD25+ regulatory T cell subset, as shown by depletion experiments. The implications of these data on the discrimination between conventional and homeostatic proliferation pathways are discussed.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
C57BL/6 (B6) background CD40-/- mice were initially obtained from D. Parker (Portland, OR), and additional CD40-/- and B6 background CD28-/- mice were obtained from The Jackson Laboratory (Bar Harbor, ME). The 4-1BBL-/- mice (19) were obtained in collaboration with J. Peschon (Immunex, Seattle, WA). BALB/c, BALB/c Rag-/-, B6, and CD45.1 congenic B6 mice (carried under the strain name B6.Ly-5.2) were obtained from the National Cancer Institute, The Jackson Laboratory, or Taconic Farms. Normal and CD28-/- DO11.10 TCR transgenic mice have been described previously (20, 21) and were maintained at the University of Minnesota. All mice were maintained under specific pathogen-free conditions and used at 6–12 wk of age. Recipient mice were maintained on antibiotic water (polymixin B sulfate and neomycin sulfate) throughout the course of the experiment.
Adoptive transfer
Cells were purified by negative selection utilizing magnetic cell sorting using MACS microbeads (Miltenyi Biotec, Auburn, CA). To purify CD44low T cell, lymph node cells were depleted from adherent cells (90-min incubation on tissue culture-treated flasks at 37°C) and labeled with FITC-coupled Abs to B220 (clone RA3-6B2), I-Ab (AF6-120.1), and CD44 (IM-7) (0.0125 µg anti-B220 and anti-I-Ab per 1 x 106 cells; 0.004 µg anti-CD44 per 1 x 106 cells) (all from BD PharMingen, San Diego, CA). In some experiments, CD4 cells were also labeled with FITC anti-CD4 (GK1.5; BD PharMingen) (0.0125 µg per 1 x 106 cells). Following staining, cells were subject to depletion using anti-FITC MACS microbeads. Flow through cells were >90% pure (established by flow cytometric analysis).
CD4+ cells from DO11.10 animals were purified utilizing a similar protocol using biotinylated (bio)3 anti-CD8 (53.6-7) plus bio-anti-B220, followed by streptavidin (SA) microbeads. In some cases, CD25+ cells were depleted at the same time using bio-anti-CD25 (7D4) (if applicable) (PharMingen). The percentage of CD4+CD25+ T cells before and after depletion was assessed by staining an aliquot of the cells with both CD25-PE Ab and SA-PE (to reveal cells bound by the depleting bio-CD25 Ab) and counterstaining for CD4 with CD4-APC or CD4-PerCP.
After purification, cells were stained with CFSE (Molecular Probes, Eugene, OR), as described previously (7, 22). Labeled donor cells were suspended in PBS, and 1–3 million cells were injected via the tail vein of recipient mice. In some cases, host mice were sublethally irradiated (700 cGy) 1 day before cell transfer. In some experiments, recipient mice were primed i.v. with 2 mg OVA (whole protein) plus 25 µg LPS (Sigma, St. Louis, MO) 1 day cell posttransfer. Cells were analyzed on day 3 postpriming.
Flow cytometry
Recipient mice were sacrificed at the time points indicated, and single cell suspensions were prepared separately from spleen and a pool of major lymph nodes. Lymph node and spleen cells were then stained with the fluorescently conjugated Abs to CD4, CD8, CD44, and CD45RB. Biotinylated Abs to CD25, CD45.1, CD45.2, CD28, and KJ1-26 (specific for the DO11.10 TCR) were used, staining being revealed using SA-TriColor, SA-PerCP, or SA-PE (all reagents from BD PharMingen). Cells were analyzed by using a FACSCalibur (BD Biosciences, San Jose, CA) and analyzed using FLOWJO (TreeStar, San Carlos, CA) software.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
To test the role of CD28/B7 interactions in regulating homeostatic expansion, we studied proliferation of CFSE-labeled normal and CD28-/- donor T cells after transfer into normal or lymphopenic B6 hosts. To minimize mouse to mouse variation, we employed a cotransfer system in which we premixed CD45.1+ wild-type and CD45.2+ CD28-/- T cells before transfer and distinguished the two donor populations during analysis with CD45 allele-specific Abs. Similar transfers were performed using CD40-/- or 4-1BBL-/- hosts to determine the effect of disrupting CD40L/CD40 and 4-1BB/4-1BBL interactions (alone or in combination with CD28 deficiency) on homeostatic expansion.
No requirement for CD28, CD40, or 4-1BBL in T cell homeostatic expansion
Using the transfer scheme outlined above, we tested whether CD28
expression on T cells and CD40 or 4-1BBL expression on host APCs was
required for T cell homeostatic expansion. As expected, neither
wild-type nor CD28-/- T cells proliferate after
transfer into unmanipulated syngeneic B6 hosts (Fig. 1
, a–d). Also as expected,
normal CD8 and CD4 T cells undergo one to four rounds of proliferation
14 days after transfer into irradiated syngeneic hosts (Fig. 1, e and g, respectively). Interestingly,
CD28-/- T cells proliferated to the same extent
as wild-type cells when transferred into irradiated wild-type hosts
(Fig. 1, f and h). This suggests that CD28 is not
required for homeostatic expansion of either CD8 or CD4 subsets.
|
, i–l) or into
4-1BBL-deficient hosts (Fig. 1, m–p). Once again,
homeostatic proliferation of both CD4 and CD8 T cell subsets was
similar regardless of CD28 expression on the donor cells and CD40 or
4-1BBL expression in the host. In all of these experiments, we observed similar donor T cell recoveries for both the normal and CD28-/- donors after expansion in the various irradiated host strains (data not shown), which argues against a survival role for these costimulator molecules in homeostatic expansion, at least in the short term.
CD28-/- DO11.10 TCR transgenic T cells undergo greater homeostatic expansion, but less Ag-driven proliferation than their CD28+ counterparts
The experiments above utilized polyclonal T cells and, although the overall degree of homeostatic expansion was similar with or without CD28, it was possible that different populations of T cells were responding, perhaps based on TCR specificity dictating CD28 dependence. Furthermore, we had to date looked exclusively in the C57BL/6 system, whereas there is some evidence that the impact of CD28/B7 deficiency is more extreme in certain BALB/c responses (25). Accordingly, we also studied homeostatic expansion of T cells from DO11.10 TCR transgenic mice, which are maintained on the BALB/c background. Data from several groups have shown that CD28 deficiency impairs the peptide/MHC (OVA/I-Ad) response of these T cells, both in vitro and in vivo (21, 26).
Thus, we transferred DO11.10 and
DO11.10/CD28-/- cells into irradiated BALB/c
hosts and analyzed their homeostatic expansion. As shown in Fig. 2, not only did we fail to see a
requirement for CD28 in DO11.10 homeostatic expansion, there was
evidence that CD28-/- DO11.10 cells proliferate
moderately better than their wild-type counterparts. The degree of this
improved response was somewhat variable between individual animals, as
exemplified in Fig. 2. Thus, at a minimum we find that more
CD28-deficient DO11 cells commit to homeostatic expansion than normal
DO11 cells (see proportions of cells undergoing zero vs three
divisions, Fig. 2a), and that in some cases this was seen as
an extra round of proliferation by the CD28-/-
DO11.10 cells (Fig. 2b).
|
, c vs b). However, as in Fig. 2, homeostatic
proliferation of the same CD28-/- DO11.10 donor
population was slightly greater than that of wild-type transgenic cells
(Fig. 3, g vs f).
|
Looking for an explanation for the slightly enhanced proliferation
of DO11.10 CD28-/- cells, we considered the
contribution of CD4+CD25+
regulatory cells (27, 28). This subset, which can suppress
autoimmune T cell responses, is underrepresented in
CD28-/- animals (29). This is also
true in mice expressing the DO11.10 TCR transgene, in which
CD28-/- DO11.10 mice have fewer
CD4+CD25+ cells compared
with wild-type DO11.10 animals (3–5% vs 5–10%, respectively; data
not shown). Thus, we tested the impact of depleting the donor DO11.10
cells of CD25+ cells. If the
CD25+ subset were restraining normal DO11.10
homeostatic expansion, then removal of these cells should lead to even
greater homeostatic expansion than seen for the
CD28-/- DO11.10 group.
CD25+ regulatory cell depletion did not improve
the robust Ag-specific T cell response in vivo, perhaps reflecting the
fact that this response was already optimal (Fig. 3d).
Interestingly, however, CD25+ subset depletion
failed to impact DO11.10 homeostatic expansion (Fig. 3, compare
h with f).
Since sublethal irradiation does not deplete all T cells in the host,
it was possible that endogenous
CD4+CD25+ cells could
influence homeostatic expansion of the transferred cells. Hence, we
also transferred these same DO11.10 populations into BALB/c
Rag-/- hosts. Similar to the results in
the irradiated hosts, proliferation of CD25-depleted DO11.10 cells did
not differ significantly from that of normal DO11.10 cells, whereas
there was once again a subtle, but consistent increase in proliferation
by the CD28-/- DO11.10 population (Fig. 4). Intriguingly, after expansion of
DO11.10 cells transferred into Rag-deficient hosts, a sizeable
proportion of the cells had proliferated sufficiently to dilute out the
CFSE dye, which was not observed in irradiated hosts (compare Fig. 4
with Figs. 2 and 3). This may relate to the fact that sublethally
irradiated hosts recover endogenous T cell numbers during the course of
the experiment (therefore limiting T cell space), whereas this will not
occur in Rag-/- hosts. We also noticed a slight
increase in the total number of donor T cells recovered after transfer
of CD25-depleted DO11.10 cells compared with wild-type or
CD28-/- cells, which was also not observed in
irradiated hosts (data not shown).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In this study, we investigated the requirement for costimulation in homeostatic expansion. The majority of our work focused on CD28, which is expressed on naive T cells and is strongly implicated in costimulating both CD4 and CD8 T cell responses (10). CD40L and 4-1BB are expressed after activation of T cells through the TCR (at least to some extent, independently of CD28 signals) (11, 12, 17, 18). Although the expression of either CD40L or 4-1BB on cells undergoing homeostatic expansion has not been addressed, there is strong evidence that this process involves TCR-mediated signals and that T cells become at least partially activated, changing expression of surface markers and changing in effector potential (9). This raises the possibility that 4-1BB and CD40L may be functionally expressed at some point during homeostatic expansion. However, in contrast to the well-documented need for costimulation in conventional naive T cell proliferative response, homeostatic expansion appears undiminished by the absence of classic costimulatory signals, mediated by CD28/B7, CD40L/CD40, or 4-1BB/4-1BBL interactions. Importantly, our results with CD28-deficient DO11.10 populations suggest that T cells can undergo homeostatic expansion regardless of whether these T cells could participate properly in an immune response to foreign Ag.
We found that CD28 was dispensable for homeostatic expansion by polyclonal or TCR transgenic T cells in irradiated or Rag-/- hosts. Using these different experimental systems minimizes the possibility that a role for CD28 is masked by either the method of host lymphocyte depletion or the TCR diversity of the donor T cell population. While we have not specifically studied whether costimulation may play a role when the degree of host lymphopenia is less severe (which might potentially raise the stringency for commitment to homeostatic expansion), it is worth noting that expansion in sublethally irradiated recipients is limited by recovery of the host T cell population; indeed, this may account for the enhanced proliferation of DO11.10 cells in Rag-/- vs irradiated hosts. Thus, the fact that we did not observe reduced expansion of CD28-/- cells in irradiated hosts argues against a role for this costimulatory pathway even in the competition for limited lymphocyte space. In any event, our data argue against a critical role for costimulation through any of these major pathways in driving homeostatic expansion.
In fact, our data suggested that lack of CD28 expression mildly
enhanced DO11.10 T cell homeostatic expansion in both sublethally
irradiated and Rag-/- hosts. It is important to
note that this effect was subtle and somewhat variable in its magnitude
(as exemplified in Fig. 2). Furthermore, we could not see consistent
evidence for enhanced proliferation of CD28-/-
polyclonal T cells (Fig. 1 and data not shown): subtle differences in
the CD28-/- population may be obscured if there
is variability in the degree of homeostatic proliferation among
polyclonal T cells (as is most likely based on analysis of numerous TCR
transgenic systems) (9, 33) or may imply that the
enhancing effect of CD28 deficiency is unique to DO11.10 T cells.
Further investigation will be needed to explore the significance of
this finding.
While our data rule out a requirement for CD28 in homeostatic expansion, it is still possible that such responses are regulated by CTLA-4, which negatively regulates T cell proliferation in response to foreign Ag. Indeed, since CD28/B7 interactions are involved (but not essential) (34, 35) for CTLA-4 expression itself, cells proliferating during homeostatic expansion may not express CTLA-4 at sufficient levels to inhibit the expansion process. This in turn may allow these cells to evade normal regulatory control.
One potential explanation for the mild positive effect of CD28
deficiency on homeostatic expansion could be the decreased
representation of CD4+CD25+
regulatory cells in CD28-/- animals
(29). However, elimination of this population in the
DO11.10 system did not result in enhanced homeostatic expansion in
either irradiated or Rag-/- recipients. These
data do not rule out the possibility that
CD4+CD25+ cells may be able
to inhibit homeostatic expansion if present in sufficient numbers or if
activated appropriately (an apparent requirement for their suppressive
effect) (36, 37). Rather, our data argue that the
endogenous CD4+CD25+
population does not inhibit homeostatic expansion, in contrast to the
proposed role of such cells in preventing autoimmune or alloreactive
responses (27, 28, 37, 38, 39). Interestingly, this might be
expected if inhibition by
CD4+CD25+ regulatory cells
was mediated through disruption of IL-2 production and/or IL-2R
up-regulation (as has been proposed; 28), since IL-2 appears not
to be important in homeostatic expansion and IL-2R is not expressed
during this response (7, 8, 40, 41). Thus, these data
further emphasize the differences in regulation that control
homeostatic expansion compared with other T cell responses.
Note added in proof.
While this manuscript was in press, Gudmundsdottir et al. (42) reported that CTLA4Ig blocked homeostatic expansion of a subset of DO11.10 Rag-/- T cells in Rag-/- recipients. Specifically, CTLA4Ig administration caused a selective loss of the rapidly proliferating subset and this inhibition was influenced by the number of donor T cells transferred. These data suggest B7 interactions might influence homeostatic proliferation of certain subsets under specific conditions, while our data argue that CD28 interactions are not obligatory for this response. The basis for these discordant results presumably lies in the different experimental approaches used.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Stephen C. Jameson, Department of Laboratory Medicine and Pathology, Center for Immunology, MMC 334, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455. E-mail address: james024{at}umn.edu
3 Abbreviations used in this paper: bio, biotinylated; SA, streptavidin.
Received for publication August 22, 2001. Accepted for publication September 19, 2001.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
TCR+ T cells. Nat. Immun. 1:107.
This article has been cited by other articles:
|
|
 |
|
  C. J. Winstead, J. M. Fraser, and A. Khoruts Regulatory CD4+CD25+Foxp3+ T Cells Selectively Inhibit the Spontaneous Form of Lymphopenia-Induced Proliferation of Naive T Cells J. Immunol., June 1, 2008; 180(11): 7305 - 7317. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Suzuki, S. Ogawa, K. Tanabe, H. Tahara, R. Abe, and H. Kishimoto Induction of Antitumor Immune Response by Homeostatic Proliferation and CD28 Signaling J. Immunol., April 1, 2008; 180(7): 4596 - 4605. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Posevitz, B. Arndt, T. Krieger, N. Warnecke, B. Schraven, and L. Simeoni Regulation of T Cell Homeostasis by the Transmembrane Adaptor Protein SIT J. Immunol., February 1, 2008; 180(3): 1634 - 1642. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kroemer, X. Xiao, M. D. Vu, W. Gao, K. Minamimura, M. Chen, T. Maki, and X. C. Li OX40 Controls Functionally Different T Cell Subsets and Their Resistance to Depletion Therapy J. Immunol., October 15, 2007; 179(8): 5584 - 5591. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-H. Cho, O. Boyman, H.-O. Kim, B. Hahm, M. P. Rubinstein, C. Ramsey, D. M. Kim, C. D. Surh, and J. Sprent An intense form of homeostatic proliferation of naive CD8+ cells driven by IL-2 J. Exp. Med., August 6, 2007; 204(8): 1787 - 1801. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhu, G. Zhu, L. Luo, A. S. Flies, and L. Chen CD137 stimulation delivers an antigen-independent growth signal for T lymphocytes with memory phenotype Blood, June 1, 2007; 109(11): 4882 - 4889. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. F. May Jr., X. Chang, H. Zhang, K. D. Lute, P. Zhou, E. Kocak, P. Zheng, and Y. Liu B7-Deficient Autoreactive T Cells Are Highly Susceptible to Suppression by CD4+CD25+ Regulatory T Cells J. Immunol., February 1, 2007; 178(3): 1542 - 1552. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Prlic, G. Hernandez-Hoyos, and M. J. Bevan Duration of the initial TCR stimulus controls the magnitude but not functionality of the CD8+ T cell response J. Exp. Med., September 4, 2006; 203(9): 2135 - 2143. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Li, X. Chang, H. Zhang, E. Kocak, C. Ding, P. Zheng, and Y. Liu Massive and destructive T cell response to homeostatic cue in CD24-deficient lymphopenic hosts J. Exp. Med., July 10, 2006; 203(7): 1713 - 1720. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Tolar, M. J. O'Shaughnessy, A. Panoskaltsis-Mortari, R. T. McElmurry, S. Bell, M. Riddle, R. S. McIvor, S. R. Yant, M. A. Kay, D. Krause, et al. Host factors that impact the biodistribution and persistence of multipotent adult progenitor cells Blood, May 15, 2006; 107(10): 4182 - 4188. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Neujahr, C. Chen, X. Huang, J. F. Markmann, S. Cobbold, H. Waldmann, M. H. Sayegh, W. W. Hancock, and L. A. Turka Accelerated Memory Cell Homeostasis during T Cell Depletion and Approaches to Overcome It. J. Immunol., April 15, 2006; 176(8): 4632 - 4639. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Mayerova, L. Wang, L. S. Bursch, and K. A. Hogquist Conditioning of langerhans cells induced by a primary CD8 T cell response to self-antigen in vivo. J. Immunol., April 15, 2006; 176(8): 4658 - 4665. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Knoechel, J. Lohr, E. Kahn, J. A. Bluestone, and A. K. Abbas Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen J. Exp. Med., November 21, 2005; 202(10): 1375 - 1386. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Zhang and G. G. Meadows Chronic alcohol consumption in mice increases the proportion of peripheral memory T cells by homeostatic proliferation J. Leukoc. Biol., November 1, 2005; 78(5): 1070 - 1080. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Jiang, F. Pan, L. M. Erickson, M.-S. Jang, T. Sanui, Y. Kunisaki, T. Sasazuki, M. Kobayashi, and Y. Fukui Deletion of DOCK2, a regulator of the actin cytoskeleton in lymphocytes, suppresses cardiac allograft rejection J. Exp. Med., October 17, 2005; 202(8): 1121 - 1130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. C. Kieper, A. Troy, J. T. Burghardt, C. Ramsey, J. Y. Lee, H.-Q. Jiang, W. Dummer, H. Shen, J. J. Cebra, and C. D. Surh Cutting Edge: Recent Immune Status Determines the Source of Antigens That Drive Homeostatic T Cell Expansion J. Immunol., March 15, 2005; 174(6): 3158 - 3163. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Sanderson, R. Scotland, P. Lee, D. Liu, S. Groshen, J. Snively, S. Sian, G. Nichol, T. Davis, T. Keler, et al. Autoimmunity in a Phase I Trial of a Fully Human Anti-Cytotoxic T-Lymphocyte Antigen-4 Monoclonal Antibody With Multiple Melanoma Peptides and Montanide ISA 51 for Patients With Resected Stages III and IV Melanoma J. Clin. Oncol., February 1, 2005; 23(4): 741 - 750. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Gilbertson, S. Germano, P. Steele, S. Turner, B. F. de St. Groth, and C. Cheers Bystander Activation of CD8+ T Lymphocytes during Experimental Mycobacterial Infection Infect. Immun., December 1, 2004; 72(12): 6884 - 6891. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Fry, M. Sinha, M. Milliron, Y.-W. Chu, V. Kapoor, R. E. Gress, E. Thomas, and C. L. Mackall Flt3 ligand enhances thymic-dependent and thymic-independent immune reconstitution Blood, November 1, 2004; 104(9): 2794 - 2800. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Li, P. Zheng, and Y. Liu CD24 Expression on T Cells Is Required for Optimal T Cell Proliferation in Lymphopenic Host J. Exp. Med., October 18, 2004; 200(8): 1083 - 1089. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Hagen, C. T. Moses, E. F. Drasler, K. M. Podetz-Pedersen, S. C. Jameson, and A. Khoruts A Role for CD28 in Lymphopenia-Induced Proliferation of CD4 T Cells J. Immunol., September 15, 2004; 173(6): 3909 - 3915. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. E. Anderson, J. M. McNiff, C. Matte, I. Athanasiadis, W. D. Shlomchik, and M. J. Shlomchik Recipient CD4+ T cells that survive irradiation regulate chronic graft-versus-host disease Blood, September 1, 2004; 104(5): 1565 - 1573. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Pazirandeh, M. Jondal, and S. Okret Glucocorticoids Delay Age-Associated Thymic Involution through Directly Affecting the Thymocytes Endocrinology, May 1, 2004; 145(5): 2392 - 2401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Cozzo, J. Larkin III, and A. J. Caton Cutting Edge: Self-Peptides Drive the Peripheral Expansion of CD4+CD25+ Regulatory T Cells J. Immunol., December 1, 2003; 171(11): 5678 - 5682. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Elflein, M. Rodriguez-Palmero, T. Kerkau, and T. Hunig Rapid recovery from T lymphopenia by CD28 superagonist therapy Blood, September 1, 2003; 102(5): 1764 - 1770. [Abstract] [Full Text] [PDF]
|
|
|
|
