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Cutting Edge: Sustained Expansion of CD8⁺ T Cells Requires CD154 Expression by Th Cells in Acute Graft Versus Host Disease¹

Janet E. Buhlmann^2,*, Mercedes Gonzalez^2,*, Brigit Ginther^*, Angela Panoskaltsis-Mortari, Bruce R. Blazar, Dale L. Greiner, Aldo A. Rossini, Richard Flavell^§ and Randolph J. Noelle^3,*

^* Department of Microbiology, Dartmouth Medical School, Lebanon, NH 03756; Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455; Diabetes Division, University of Massachusetts Medical School, Worcester, MA 01605; and ^§ Department of Immunobiology, Yale University, New Haven, CT 06520

	Abstract

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Brief treatment with CD154 Ab has been shown to prevent acute graft versus host disease (aGvHD). We extend these data to show that in the absence of CD154 function, donor T cells are unable to expand or generate high level anti-host CTL activity. Using transgenic (Tg) alloreactive CD8⁺ T cells adoptively transferred into allogeneic recipients, we show that short-term expansion of the CD8⁺ Tg T cells occurred in the absence of Th cells, and this short-term expansion could be facilitated with an agonistic CD40. While CD40 agonism could enhance short-term expansion, sustained expansion of CD8⁺ Tg T cells required bona fide CD154-expressing CD4⁺ alloreactive Th cells. While CD154 was necessary for CD8⁺ Tg T cell sustained expansion, IL-2 was also implicated as essential. These observations suggest CD154 therapy in GvHD is effective because the treatment causes an abortive CD8 alloresponse leading to the exhaustion or deletion of alloreactive CD8⁺ clones preventing the development of disease.

	Introduction

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Graft versus host disease (GvHD)⁴ is an iatrogenic immunopathologic disorder originated after transfer of immunocompetent lymphocytes to hosts expressing allogeneic Ags (1). GvHD is the major clinical barrier to successful bone marrow transplantation in humans. One murine model used to study this disease is the transfer of C57BL/6 (H-2^b) parental cells into a C57BL/6 x DBA/2 (H-2^bxd)F₁ recipient (2, 3, 4). Initiation of the disease results from the recognition of host MHC molecules by alloreactive donor T cells and the subsequent generation of anti-host activity (2, 3, 4). In the second week after parental cell transfer, acute GvHD (aGvHD) was shown to correlate with an increase in IFN- production by both CD4⁺ and CD8⁺ donor T cells and the expansion of donor anti-host CD8⁺ T cells. The expanding CD8⁺ cells eliminate host B cells and cause an overall reduction in splenic cellularity (5).

Previous studies have shown that a brief treatment with CD154 at the time of parental cell transfer was able to block the development of both chronic and acute forms of GvHD (6, 7). The studies presented here were undertaken to gain insights into the mechanisms by which blockade with CD154 interferes with the development of GvHD. The data show that in the absence of CD154 function, donor T cells are unable to accumulate or generate high levels of anti-host CTL. Furthermore, it was shown that an agonistic CD40 mAb was able to enhance the short-term expansion of TCR transgenic (TCR Tg) CD8⁺ T cells specific for host alloantigen. However, sustained expansion of the TCR Tg T cells requires help provided by donor IL2-producing, CD154-expressing CD4⁺ T cells.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Mice

Six- to 8-wk-old (C57BL/6 x DBA/2)F₁ (B6D2F₁) and C57BL/6 (B6) mice were obtained from the National Cancer Institute (Bethesda, MD). IL-2^-/- mice were obtained from The Jackson Laboratory (Bar Harbor, ME). The CD154^-/- mice (in a mixed background C57BL/6 x 129) were produced as previously described (8). 2C TCR Tg mice were kindly provided by Dr. D. Loh (University of Minnesota, Minneapolis, MN). Animals were maintained in the specific pathogen-free animal facility at Dartmouth Medical School.

Antibodies

MR1 (hamster CD154 (9)), 1B2 (the clonotypic -2C TCR, kindly donated by Dr. H. N. Eisen, Massachusetts Institute of Technology, Cambridge, MA), and FGK115 (rat CD40, a kind gift of T. Rolink, Basel Institute, Basel, Switzerland) were produced as ascites and purified by HPLC. CD8-PE mAb was obtained from PharMingen (San Diego, CA).

Induction of GvHD

Spleens from either C57BL/6, CD154^-/-, or their wild-type H-2^b/b littermates were aseptically removed and teased into a single-cell suspension. B6D2F1 (H-2^d/b) recipients were injected i.v. with 10⁸ donor cells. Mice were injected i.p. with either CD154 or hamster Ig, 250 µg/mouse/day, on days 0, 2, and 4 unless otherwise indicated. For studies using CD40, mice were injected with 10 µg/mouse/day every other day starting day 0 until they were sacrificed.

Assessment of CTL activity in vitro

Spleen cells from in vivo-primed animals treated with CD154 or untreated were rechallenged in vitro with mytomicin C-treated spleen cells from B6D2F₁ mice. After 6 days the cultures were harvested, and the resulting live cells were used as effectors in the standard 4-h ⁵¹Cr release assay (6).

Adoptive transfer of L^d-reactive TCR Tg 2C TCR CD8⁺ T cells

Lymphocytes from 2C TCR Tg mice were transferred i.v. (4–8 x 10⁶ Tg⁺ cells per recipient). In some experiments the 1B2⁺ Tg cells were enriched by panning on goat anti-mouse Ig-coated plates. In addition to Tg cells, some mice were given 25 x 10⁶ C57BL/6 spleen cells or 20 x 10⁶ C57BL/6 CD4⁺ T cells enriched by panning and CD8⁺ complement kill. To follow the expansion of the transferred Tg cells, lymphocytes from recipient spleens were harvested at different times and stained with 1B2-FITC and CD8-PE. Flow cytometry data was acquired using a FACScan (Becton Dickinson, Mountain View, CA).

	Results and Discussion

Top Abstract Introduction Materials and Methods Results and Discussion References

 
CD154 on donor T cells is essential for GvHD-associated mortality

Previous studies from our laboratory established that treatment of mice with CD154 blocked aGvHD (6). These observations were extended to address the question of whether CD154 expression on the donor T cells was critical for inducing aGvHD. To this end, donor T cells from CD154^-/- mice were transferred into F₁ recipients. Results showed that animals given CD154^+/+ cells died rapidly, with the average onset of death by day 21, and only 15% of the animals surviving out to day 60 (Fig. 1A). In contrast, for recipient mice given CD154^-/- cells, the first death was not seen until day 37, and at day 60, 92% of the animals were still alive. Therefore, expression of CD154 on donor T cells is critical for the development of disease.

View larger version (19K): [in this window] [in a new window]   FIGURE 1. A, Reduced GvHD lethality in the absence of CD154 function. F1 mice were given CD154-/- or CD154+/+ spleen cells and mortality was monitored during 2 mo. One group of CD154+/+ recipients received 250 µg of anti-CD154, i.p, on days 0, 2, and 4. Donor cells: CD154-/- (, n = 13), CD154+/+ (•, n = 13), and CD154+/+ plus anti-CD154 (, n = 10). B, Survival from GvHD with a single dose of anti-CD154. Mice were given cells from C57BL/6 mice. After cell transfer, recipients were either left untreated (•, n = 10) or given a single dose of anti-CD154 (, n = 11), 250 µg i.p., on day 0. Mortality was monitored.

CD40-CD154 signaling is essential for donor cell expansion and the development of CTL activity in GvHD

Although it is clear that mortality was reduced in the absence of CD154 function, other cellular aspects of GvHD were examined. To determine whether CD154^-/- cells were capable of inducing CTL activity associated with GvHD, spleen cells from CD154^-/- (C57BL/6 x 129) or CD154^+/+ (C57BL/6 x 129) mice were transferred into B6D2F₁ recipients. On day 12, the animals were sacrificed and spleen cells were cocultured for 6 days with cells from B6D2F₁ to restimulate the alloreactive CTL generated in vivo. Secondary anti-allogeneic CTL activity was determined in a standard 4-h ⁵¹Cr release assay. Spleen cells from recipients given CD154^+/+ cells exhibited high levels of anti-allogeneic CTL activity. In contrast, spleen cells from animals given CD154^-/- cells had no detectable CTL activity (Fig. 2A). The lack of CTL activity in CD154^-/- recipients is not due to an intrinsic defect in the ability of CD154^-/- CD8⁺ T cells to generate CTL effector cells. Naive CD154^-/- cells cultured in vitro for 6 days with F₁ stimulators were capable of generating anti-H-2^d lytic activity at a similar level to cells from wild-type mice (Fig. 2A).

View larger version (24K): [in this window] [in a new window]   FIGURE 2. CD154-/- cells do not generate alloreactive CTLs in aGvHD. A, B6D2F1 recipients were given the equivalent of 1 spleen i.v. of either CD154-/- cells or CD154+/+ cells, and on day 12 the animals were sacrificed. After 1 wk of in vitro culture with B6D2F1 spleen cells, allogeneic CTL activity was determined in a standard 4-h 51Cr release assay using cells obtained from CD154+/+ recipients (•), CD154-/- recipients (), naive CD154+/+ cells () and naive CD154-/- cells (). B, Decreased splenic cellularity is dependent on CD154. Total numbers of viable spleen cells were measured from B6D2F1 mice which received CD154+/+, or CD154-/- () spleen cells. Mice receiving CD154+/+ spleen cells were treated with HIg (•) or with anti-CD154 (). Data in all panels are representative of three such experiments with three mice per group.

CD154 is essential for the expansion of alloreactive CD8⁺ T cells

To assess the possible role of CD154 on the expansion of alloreactive CD8⁺ T cells, a model employing alloreactive, Tg T cells was used. 2C TCR Tg mice express a TCR on CD8⁺ T cells which is reactive to H-2L^d (10). CD8⁺ Tg T cells (4–8 x 10⁶/mouse) were adoptively transferred into either syngeneic C57BL/6 (H-2^b) or Ag-bearing F₁ (H-2^b/d) mice, and expansion of the Tg cells was followed using a clonotypic mAb by flow cytometry. Following adoptive transfer, mice were treated with either an agonistic CD40 to facilitate expansion or CD154 to block expansion. At time points after cell transfer, the recipients were sacrificed and the number of CD8⁺ Tg T cells was determined.

As can be seen in Fig. 3, upon adoptive transfer of CD8⁺ Tg T cells into an F₁ recipient, there is a transient expansion of these cells. The expansion of Tg T cells is observed by day 4 posttransfer but is self-limited, diminishing to 1 x 10⁶ cells/spleen at day 8 and reaching basal levels similar to syngeneic B6 hosts (0.1 x 10⁶ 2C TCR cells/spleen) by days 10–12 after transfer (Fig. 3). Coadministration of an agonistic CD40 augmented the early expansion observed on days 4 and 8. However, CD40 did not enhance the long-term expansion of the Tg T cells when measured on day 12.

View larger version (27K): [in this window] [in a new window]   FIGURE 3. Kinetics of the expansion of anti-Ld specific 2C TCR Tg CD8+ cells after adoptive transfer to Ag-bearing H-2b/d F1 hybrids. Each recipient mouse was injected i.v. with 4–8 x 106 2C TCR Tg cells. Mice from some groups received an additional 20 x 106 purified CD4+ from wild-type, CD154-/-, or IL-2-/- C57BL/6 donors. Additionally, groups as indicated were treated with either CD154 or CD40 as indicated in Materials and Methods. At different points after cell transfer, lymphocytes were collected from the spleen and the number of Tg cells calculated by multiplying the total number of viable cells by the percentage of CD8+ IB2+ determined by flow cytometry.

To establish that CD154 expression on the alloreactive CD4⁺ T cells was critical for CD8⁺ Tg T cell expansion, CD154^+/+ (129 x B6)F₁ or CD154^-/- (129 x B6)F₁ CD4⁺ T cells were cotransferred with CD8⁺ Tg T cells. The intensity of the alloreactive response by the CD154^+/+ CD4⁺ was less than that observed by CD4⁺ T cells on a B6 genetic background. Nonetheless, unlike CD154^+/+ cells, the CD154^-/- CD4⁺ T cells were completely ineffective at supporting CD8⁺ Tg T cell expansion.

The data show that alloreactive, CD154-expressing T cells are necessary, but CD40 triggering alone is not sufficient for sustained expansion of CD8⁺ Tg T cells. Additional support for this conclusion is provided by studies showing that T cells from IL-2^+/+ mice, but not from IL-2^-/- mice will support CD8⁺ Tg T cells expansion. Thus, in addition to CD154, IL-2 appears to be another factor critical for the sustained expansion of the CD8⁺ Tg T cell population (Fig. 3).

The stimulation of alloreactive CD8⁺ T cells in the absence of CD4⁺ cell help appeared to result in long-term CD8 anergy. A previous study (11) showed that when 2C TCR Tg T cells were adoptively transferred into an Ag-bearing host, a large percentage of them apoptosed after a transient, abortive expansion. Our own studies show that the abortive expansion of the Tg T cells observed on day 4 was not dependent on CD154 (data not shown); however, CD40 potentiated the short-term expansion. Thus, short-term expansion of the CD8⁺ Tg T cells is CD154-independent but can be potentiated by CD40 triggering.

Recently, a number of reports have shown that CD40 replaced T cell help in the development of CD8⁺ T cell responses. The generation of cytotoxic T cell responses specific to OVA (12), adenovirus E1B peptide (13), or H-Y (14) was enhanced by CD40. We (15) and others (12, 14), have suggested that CD154-induced maturation of dendritic cells may be a critical event inducing CTL responses. Interestingly, blocking B7.1 and B7.2 signaling (16, 17, 18) or neutralizing IL-12 (19) has been shown to ameliorate GvHD. While we support the view that CD40 signaling of APCs is likely an essential element in driving CD8⁺ T cell expansion, CD40 agonism cannot completely mimic the physical presence of CD4⁺ cells. In the model presented, we show that the expansion in vivo of alloreactive Tg T cells is enhanced for only a short period of time by CD40, with the number of Tg cells falling to basal levels by day 10–12 after injection. In contrast, a large number of CD8⁺ Tg cells persists by day 10–12 in the mice that had received bona fide alloreactive CD154⁺ CD4⁺ T cells as a source of help. Furthermore, we show that IL-2 production by alloreactive CD4⁺ T cells is also critical for CD8 expansion. Taken together, these observations suggest that the maturation of dentric cells by CD154 (or CD40) is essential for CD8⁺ T cell expansion but Th cells provide stimuli in addition to CD154 which are necessary to sustain the expansion of CD8⁺ T cells in vivo

It can be suggested that in the absence of CD154 function, factors required for the survival of alloreactive CD8⁺ T are not produced and these cells die and/or become anergic. Such a conclusion is consistent with the data presented and studies in another GvHD model whereby perforin mRNA-expressing T cells were undetectable in CD154-treated recipients (7). With regard to the impact of CD154 blockade on the CD4 compartment, CD154 treatment also has been shown to impair the expansion of the alloreactive CD4 compartment and reduce the frequency of inflammatory T cells expressing mRNA for IL-2, IL-12 p40, and IFN- mRNA (7). Therefore, because of the loss of alloreactive CD8⁺ T cells and the skewing and reduced expansion of alloreactive CD4⁺ T cells, long-term tolerance is observed when CD154 function is impaired. Such observations provide a rationale basis for the use of CD154 in the management of GvHD in humans.

	Acknowledgments

 
Flow cytometry was done at Dartmouth Medical School in the Herbert C. Englert Cell Analysis Laboratory, which was established by a grant from the Fannie E. Rippel Foundation and is supported in part by the Core Grant of the Norris Cotton Cancer Center (CA 23108).

	Footnotes

 
¹ This work was supported by National Institutes of Health Grants P01 DK/AI53006 (R.J.N., D.L.G., and A.A.R) and AI37075 and AI53006 (R.J.N.).

² J.E.B. and M.G. contributed equally to this work.

³ Address correspondence and reprint requests to Randolph J. Noelle, Department of Microbiology, Dartmouth Medical School, 1 Medical Center Drive, Lebanon, NH 03756. E-mail address:

⁴ Abbreviations used in this paper: GvHD, graft versus host disease; aGvHD, acute GvHD; Tg, transgenic; B6D2F₁, (C57BL/6 x DBA/2)F₁; B6, C57BL/6.

Received for publication December 1, 1998. Accepted for publication January 27, 1999.

	References

Top Abstract Introduction Materials and Methods Results and Discussion References

 

1. Gleichmann, E. S., S. T. Pals, A. G. Rolink, T. Radaszkiewicz, H. Gleichmann. 1984. Graft-versus-host reactions: clues to the etiopathology of a spectrum of immunological diseases. Immunol. Today 5:324.
2. Via, C. A., G. M. Shearer. 1988. T-cell interactions in autoimmunity: insights from a murine model of graft-versus-host disease. Immunol. Today 9:207.[Medline]
3. Rolink, A. G., S. T. Pals, E. Gleichmann. 1983. Allosupressor and allohelper T cells in acute and chronic graft-versus host (GVH) disease. II F1 recipients carrying mutation of H-2K and/or I-A. J. Exp. Med. 157:755.[Abstract/Free Full Text]
4. Rolink, A. G., E. Gleichmann. 1983. Allosupressor and allohelper T cells in acute and chronic graft-versus host (GVH) disease. III. Different Lyt subsets of donor T cells induce different pathological syndromes. J. Exp. Med. 158:546.[Abstract/Free Full Text]
5. Rus, V., A. Svetic, P. Nguyen, W. C. Gause, C. S. Via. 1995. Kinetics of Th1 and Th2 cytokine production during the early course of acute and chronic murine graft-versus-host disease: regulatory role of donor CD8⁺ T cells. J. Immunol. 155:2396.[Abstract]
6. Durie, F. H., A. Aruffo, J. A. Ledbetter, K. M. Crassi, W. R. Green, R. J. Noelle. 1994. Antibody to the ligand of CD40, gp39, blocks the occurrence of the acute and chronic forms of graft-versus-host disease. J. Clin. Invest. 94:1333.
7. Blazar, B. R., P. A. Taylor, A. Panoskaltsis-Mortari, J. Buhlmann, J. Xu, R. A. Flavell, R. Korngold, R. Noelle, D. A. Vallera. 1997. Blockade of CD40 ligand-CD40 interaction impairs CD4⁺ T cell-mediated alloreactivity by inhibiting mature donor T cell expansion and function after bone marrow transplantation. J Immunol 158:29.[Abstract]
8. Xu, J., T. M. Foy, J. D. Laman, J. J. Dunn, T. J. Waldschmidt, J. Elsemore, R. J. Noelle, R. A. Flavell. 1994. Mice deficient for the CD40 ligand. Immunity 1:423.[Medline]
9. Noelle, R. J., M. Roy, D. M. Shepherd, I. Stamenkovic, J. A. Ledbetter, A. Aruffo. 1992. A novel ligand on activated T helper cells binds CD40 and transduces the signal for the cognate activation of B cells. Proc. Natl. Acad. Sci. USA 89:6550.[Abstract/Free Full Text]
10. Sha, W. C., C. A. Nelson, R. D. Newberry, D. M. Kranz, J. H. Russell, D. Y. Loh. 1988. Selective expression of an antigen receptor on CD8-bearing T lymphocytes in transgenic mice. Nature 335:271.[Medline]
11. Zhang, L.. 1996. The fate of adoptively transferred antigen-specific T cells in vivo. Eur. J. Immunol. 26:2208.[Medline]
12. Bennett, S. R. M., F. R. Carbone, F. Karamalis, R. A. Flavell, J. F. Miller, W. R. Heath. 1998. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393:478.[Medline]
13. Schoenberger, S. P., R. E. M. Toes, E. I. H. van der Voort, R. Offringa, C. J. M. Melief. 1998. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393:480.[Medline]
14. Ridge, J. P., F. Di Rosa, P. Matzinger. 1998. A conditioned dendritic cell can be a temporal bridge between a CD4⁺ T-helper and a T-killer cell. Nature 393:474.[Medline]
15. Mackey, M. F., J. R. C. Gunn, C. Maliszewski, H. Kikutani, R. J. Noelle, R. Barth. 1998. Dendritic cells require maturation via CD40 to generate protective antitumor immunity. J. Immunol. 161:2094.[Abstract/Free Full Text]
16. Blazar, B. R., P. A. Taylor, P. S. Linsley, D. S. Vallera. 1994. In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice. Blood 83:3815.[Abstract/Free Full Text]
17. Blazar, B. R., P. A. Taylor, G. S. Gray, D. A. Vallera. 1994. The role of T cell subsets in regulating the in vivo efficacy of CTLA4-Ig in preventing graft-versus-host disease in recipients of fully MHC or multiple minor histocompatibility-disparate donor inocula. Transplantation 58:1422.[Medline]
18. Hakim, F. T., R. Cepeda, G. S. Gray, C. H. June, R. Abe. 1995. Acute graft-versus-host reaction can be aborted by blockade of costimulatory molecules. J. Immunol. 155:1757.[Abstract]
19. Williamson, E., P. Garside, J. A. Bradley, A. Mowat. 1996. IL-12 is a central mediator of acute graft versus host disease. J. Immunol. 157:689.[Abstract]

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				N. D. Jones, A. Van Maurik, M. Hara, B. M. Spriewald, O. Witzke, P. J. Morris, and K. J. Wood CD40-CD40 Ligand-Independent Activation of CD8+ T Cells Can Trigger Allograft Rejection J. Immunol., July 15, 2000; 165(2): 1111 - 1118. [Abstract] [Full Text] [PDF]

				E. J. Wagar, M. A. Cromwell, L. D. Shultz, B. A. Woda, J. L. Sullivan, R. M. Hesselton, and D. L. Greiner Regulation of Human Cell Engraftment and Development of EBV-Related Lymphoproliferative Disorders in Hu-PBL-scid Mice J. Immunol., July 1, 2000; 165(1): 518 - 527. [Abstract] [Full Text] [PDF]

				N. C. Matthews, M. Wadhwa, C. Bird, F. E. Borras, and C. V. Navarrete Sustained Expression of CD154 (CD40L) and Proinflammatory Cytokine Production by Alloantigen-Stimulated Umbilical Cord Blood T Cells J. Immunol., June 15, 2000; 164(12): 6206 - 6212. [Abstract] [Full Text] [PDF]

				I. Okamoto, K. Kohno, T. Tanimoto, K. Iwaki, T. Ishihara, S. Akamatsu, H. Ikegami, and M. Kurimoto IL-18 Prevents the Development of Chronic Graft-Versus-Host Disease in Mice J. Immunol., June 1, 2000; 164(11): 6067 - 6074. [Abstract] [Full Text] [PDF]

				X.-Z. Yu, S. J. Bidwell, P. J. Martin, and C. Anasetti CD28-Specific Antibody Prevents Graft-Versus-Host Disease in Mice J. Immunol., May 1, 2000; 164(9): 4564 - 4568. [Abstract] [Full Text] [PDF]

				S. O. Andreasen, J. E. Christensen, O. Marker, and A. R. Thomsen Role of CD40 Ligand and CD28 in Induction and Maintenance of Antiviral CD8+ Effector T Cell Responses J. Immunol., April 1, 2000; 164(7): 3689 - 3697. [Abstract] [Full Text] [PDF]

				E. Seung, N. Iwakoshi, B. A. Woda, T. G. Markees, J. P. Mordes, A. A. Rossini, and D. L. Greiner Allogeneic hematopoietic chimerism in mice treated with sublethal myeloablation and anti-CD154 antibody: absence of graft-versus-host disease, induction of skin allograft tolerance, and prevention of recurrent autoimmunity in islet-allografted NOD/Lt mice Blood, March 15, 2000; 95(6): 2175 - 2182. [Abstract] [Full Text] [PDF]

				N. Garceau, Y. Kosaka, S. Masters, J. Hambor, R. Shinkura, T. Honjo, and R. J. Noelle Lineage-Restricted Function of Nuclear Factor {kappa}B-Inducing Kinase (Nik) in Transducing Signals via Cd40 J. Exp. Med., January 17, 2000; 191(2): 381 - 386. [Abstract] [Full Text] [PDF]

				L. Lefrancois, J. D. Altman, K. Williams, and S. Olson Soluble Antigen and CD40 Triggering Are Sufficient to Induce Primary and Memory Cytotoxic T Cells J. Immunol., January 15, 2000; 164(2): 725 - 732. [Abstract] [Full Text] [PDF]

				L. Lefrancois, S. Olson, and D. Masopust A Critical Role for Cd40-Cd40 Ligand Interactions in Amplification of the Mucosal Cd8 T Cell Response J. Exp. Med., November 1, 1999; 190(9): 1275 - 1284. [Abstract] [Full Text] [PDF]

				D. M. Shepherd and N. I. Kerkvliet Disruption of CD154:CD40 Blocks Generation of Allograft Immunity Without Affecting APC Activation J. Immunol., September 1, 1999; 163(5): 2470 - 2477. [Abstract] [Full Text] [PDF]

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