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-Dependent Mechanism1
* Division of Bone Marrow Transplant, University of Minnesota Cancer Center and Department of Pediatrics, Minneapolis, MN 55455;
Wyeth Research, Cambridge, MA 02140;
Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan; and
¶ Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138
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Abstract |
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production was required for optimal GVHD acceleration in the absence of PD-1 ligation. These data indicate that PD-1 ligation down-regulates GVHD through modulation of IFN- production and suggest a novel therapeutic target for inhibiting GVHD lethality. |
Introduction |
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PD-L1, also termed B7-H1, is a member of the B7 family (6). PD-L1 is expressed on endothelium, thymic epithelium, and some activated T cells. PD-L2, also termed B7-DC, is expressed in pancreas, lung, and liver. Both PD-L1 and PD-L2 are expressed on monocytes, dendritic cells, and keratinocytes. Notably, with the exception of the pancreas, these organs are targets of GVHD. In addition, PD-L1 and PD-L2 are expressed in heart and skeletal muscle. IFN- up-regulates PD-L1 and to a lesser extent PD-L2 expression in monocytes (12), dendritic cells, and keratinocytes and PD-L1 expression in endothelium.
Although PD-1-/- mice are prone to autoimmunity, the effects of PD-1 signaling on T cell responses remain controversial. In vitro studies have attributed either a stimulatory (5, 7) or an inhibitory (6, 11, 13) function to this pathway. Little is known as to how PD-1/PD-L regulates T cell responses in vivo. To further define the function of the PD-1 pathway in vivo and to specifically analyze the effects of PD-1/PD-L interaction on regulating graft-vs-host disease (GVHD), studies were performed using irradiated recipients of allogeneic donor cells. Our studies demonstrate that PD-1 blockade potently enhances T cell alloresponses in vitro and in vivo. The effects of PD-1/PD1-L blockade were not dependent on the expression of perforin or Fas ligand (FasL) but were largely dependent upon IFN- production. These data have important implications for solid organ and hemopoietic stem cell transplantation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 (termed B6) (H2b) mice were purchased from the National Institutes of Health. B10.BR/SgSnJ (H2k), B6.C-H2bm12/KhEg (termed bm12), B6.C-H2bm1/KhEg (termed bm1), B6.129S7-Ifngtm1Ts (termed B6 IFN--/-), C57BL/6-Pfptm1Sdz (termed B6 perf-/-), and B6Smn.C3-Tnfsf6gld (termed B6 gld) mice were purchased from The Jackson Laboratory (Bar Harbor, ME). bm12 and bm1 mice have mutant MHC class II and class I alleles, respectively, that differ from those of B6 mice. Mice were bred and housed in a specific pathogen-free facility in microisolator cages. PD-1-/- mice were generated as described and backcrossed over 11 generations with B6 mice (14). Donors and recipients were used at 8–12 wk of age.
GVHD generation
B10.BR recipients were irradiated with 8.0 Gy of total body irradiation on day -1. Donor bone marrow (BM) (20 x 106), depleted of T cells using anti-Thy-1.2 plus rabbit complement treatment, was infused on day 0 (15). To induce GVHD, donor splenocytes from various strains were infused at the doses indicated. To determine the effects of the PD-1/PD-L pathway on CD4+ or CD8+ T cell-mediated GVHD lethality, bm12 or bm1 recipients were sublethally irradiated (6.0 Gy of total body irradiation) and given CD4+ or CD8+ T cells, respectively, from B6 or B6 PD-1-/- donors. Mice were weighed twice weekly and monitored daily for survival and clinical evidence of GVHD (ruffled fur, cachexia, alopecia, diarrhea).
mAb and fusion protein administration
The hamster anti-murine PD-1, clone J43 (3), and anti-murine CTLA-4, clone C10-4F10--1, mAbs have been described. Control hamster IgG was purchased (Rockland Laboratories, Gilbertsville, PA). The generation and production of murine PD-L1.Ig protein, which consists of the extracellular domains of murine PD-L1 linked to the hinge-CH2-CH3 domains of a mutated murine IgG2a to reduce FcR and complement binding, have been described (6). Murine anti-human CTLA4 mAb (mouse IgG2a) was used as a control. mAbs and fusion proteins were administered at 200 µg/dose i.p. from days -1 to +5 and then three times weekly through day +28.
GVHD target tissue analysis
GVHD organs were snap-frozen in liquid nitrogen and stored at 80°C. Frozen sections were cut 4 µm thick and fixed for 5 min in acetone. Cryosections were stained using biotinylated mAbs (anti-CD4-, anti-CD8-, anti-H2b- and anti-H2k) (BD PharMingen, San Diego, CA), avidin-biotin blocking reagents, ABC-peroxidase conjugate, and diaminobenzidine chromogenic substrate (Vector Laboratories, Burlingame, CA) and CD4+ and CD8+ T cells were enumerated (16). Representative sections from each block were stained with hematoxylin and eosin for assessment of GVHD using a published semiquantitative scoring system (17).
MLR cultures
Purified T cells from PD-1-/- and wild-type (WT) B6 mice (5 x 105 cells/well) were stimulated with 48-h LPS-activated and irradiated (2000 cGy) B10.BR splenocytes at various responder-stimulator ratios. Cultures were labeled with [3H]thymidine (1 µCi) for the last 24 h of a 3-day assay.
Cytokine analysis
MLR supernatants or sera were obtained from cohorts of mice for cytokine analysis (IL-2, IL-4, IL-10, TNF-
, IFN-) using a cytometric bead assay (BD PharMingen) according to the manufacturer’s specifications.
Statistical analysis
The Kaplan-Meier product-limit method was used to calculate survival rates. Differences between groups were determined using log rank analysis. Cytokine data were analyzed by Student’s t test. Values of p 
0.05 were considered significant.
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Results |
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To determine whether targeting PD-1/PD-L interaction would affect GVHD-induced mortality, lethally irradiated B10.BR recipients were given B6 bone marrow plus supplemental splenocytes (0 or 5 x 106) and either irrelevant or PD-L1.Fc fusion protein consisting of the extracellular domains of murine PD-L1 linked to a mutated murine IgG2a. Recipients given PD-L1.Fc fusion protein had a significant acceleration in GVHD-induced mortality (p < 0.02), equivalent to the administration of a 3-fold higher spleen cell dose (Fig. 1A). In other studies, recipients were given either irrelevant or blocking anti-PD-1 mAb. Anti-PD-1 mAb infusion markedly accelerated GVHD lethality (p < 10-6) which was significantly (p = 0.03) greater than the GVHD rate observed in recipients of a 3-fold higher splenocyte dose (Fig. 1B). Because PD-L1.Fc and anti-PD-1 mAb infusion could be functioning either to provide a positive or to preclude a negative costimulatory signal to donor T cells, experiments were performed comparing GVHD lethality of supplemental B6- PD-1+/+ to B6-PD-1-/- splenocytes (5 or 15 x 106) (Fig. 1C). The GVHD lethality of B6-PD-1-/- splenocytes was markedly accelerated compared with B6 WT cells (p < 0.0001). The magnitude of GVHD acceleration was similar to that observed with either PD-L1.Fc or anti-PD-1 mAb. Together, these data suggest that PD-L1.Fc and anti-PD-1 mAb both blocked PD-1 ligation and inhibited a negative costimulatory signal to donor T cells.
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3-fold with PD-1-/- CD4+ or CD8+ T cells as compared with results obtained using B6 donors (Fig. 1, D and E). In aggregate, our studies provide conclusive evidence that prohibiting PD-1 engagement accelerated GVHD lethality. The inhibitory effects of the PD-1/PD-L pathway on GVHD-induced mortality are not redundant with the CTLA-4:B7 pathway
The down-regulatory effects of the PD-1/PD-L pathway on GVHD parallel our previous observations for the CTLA-4/B7 pathway under these same conditions (15). To determine whether these pathways are fully redundant, B10.BR recipients were given B6-PD-1+/+ BM, a low dose of splenocytes (5 x 106), and either irrelevant mAb or anti-PD-1, anti-CTLA-4, or both mAbs. Whereas anti-CTLA-4 mAb did not significantly accelerate GVHD lethality at this T cell dose (p = 0.41), anti-PD-1 mAb did, reducing the median survival time by 2 wk as compared with controls (p = 0.002). Importantly, the combined administration of both mAb was significantly more potent than either alone in accelerating GVHD lethality (p < 0.04; Fig. 2). These data indicate that the PD-1/PD-L, and CTLA-4/B7 pathways are not redundant and suggest a major regulatory role for the PD-1/PD-L pathway in GVHD modulation.
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On day 7 post-bone marrow transplant (BMT), tissues were obtained for GVHD scoring, using a semiquantitative scoring system (0
4) from representative recipients that received irrelevant or anti-PD-1 mAb and 5 x 106 splenocytes. In the liver, irrelevant mAb treated recipients had less severe injury than anti-PD-1 mAb-treated mice (2.5 vs 3.3, respectively; p = 0.01). Mean GVHD scores were not significantly different in colon, skin, or lung (not shown).
FasL has been implicated in GVHD pathogenesis and especially hepatic GVHD (16, 18). To determine whether FasL expression was required for the accelerated GVHD lethality observed with anti-PD-1 mAb infusion, heavily irradiated B10.BR recipients were given B6 BM and supplemental splenocytes from FasL-/- (gld/gld) donors (Fig. 3A). Although GVHD lethality was delayed after the administration of FasL-/- donor splenocytes, anti-PD-1 mAb still accelerated GVHD. Because perforin-mediated cytolysis also has been implicated in GVHD pathogenesis, studies were performed using perforin-/- donor splenocytes (Fig. 3B). Similar to FasL-/- donor splenocytes, GVHD lethality was accelerated by anti-PD-1 mAb given to recipients of perforin-/- splenocytes. Thus, the mechanism(s) involved in PD-1-mediated GVHD regulation is not dependent on FasL or perforin.
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production is required for optimal GVHD acceleration induced by PD-1/PD-L blockadeBecause two of the classical cytolytic effector pathways, perforin and FasL, did not appear to be essential for GVHD acceleration induced by PD-1/PD-L blockade, we explored the possibility that enhanced proliferative responses and/or the release of proinflammatory cytokines may provide an explanation for our findings. A previous report has shown that PD-1/PD-L ligation of naive CD4+ and CD8+ T cells led to decreased proliferation (13). In addition, 2C PD-1-/- T cells show enhanced proliferation on repeated stimulation with H2Ld-derived splenocytes (4). However, the effect of the PD-1 pathway in primary MLR responses has not been examined. Thus, primary MLR cultures were established using responder T cells from WT vs PD-1-/- B6 mice and LPS blasts from B10.BR mice as stimulators at various ratios. WT T cells isolated during the MLR culture were PD-1+, whereas virtually all LPS blasts were PD-L1+ (data not shown). Primary MLR cultures did not consistently reveal significantly higher proliferation of PD-1-/- vs WT T cells (Fig. 4A), suggesting that the PD-1/PD-L pathway does not play a major role in regulation of proliferation in primary MLR responses.
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; TNF-) and anti-inflammatory (IL-4; IL-5) cytokines (Fig. 4B and Table I). In primary MLR cultures, IFN- was substantially increased in cultures containing PD-1-/- T cells (Fig. 4B). On sera collected post-BMT, IFN- levels were significantly higher on days 4 and 6 post-BMT in anti-PD-1 mAb-treated recipients (Table I).
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production was observed in vitro with PD-1-/- T cells and in vivo upon anti-PD-1 treatment, we next performed studies using B6 IFN--/- or WT donor splenocytes administered to irrelevant or anti-PD-1 mAb-treated B10.BR recipients (Fig. 4C). As we have previously reported, IFN--/- splenocytes result in substantial acceleration of GVHD mortality relevant to WT splenocytes (19), likely due to defective T cell apoptosis (20). Whereas recipients of WT splenocytes had a substantial acceleration in GVHD lethality induced by anti-PD-1 vs irrelevant mAb (median survival time, 14 vs 31 days; p < 0.02), there was no significant effect in recipients of IFN--/- splenocytes (median survival time, 19 vs 24 days; p = 0.42). These data are consistent with a requirement of donor IFN- production in the GVHD-accelerating effect of anti-PD-1 mAb. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The effect of PD-1/PD-L interactions on down-regulating T cell responses in vivo has striking similarities to CTLA-4/B7 interactions. Both PD-1-/- and CTLA4-/- mice develop a lymphoproliferative syndrome with organ infiltration by activated T cells, although this process is more rapid in CTLA4-/- mice (4, 9, 10, 14). PD-1 engagement inhibits cell cycle progression, similar to CTLA-4 engagement (13, 23). A failure of cell cycle progression has been associated with multiple forms of anergy. Conversely, CTLA-4 engagement has been shown to promote tolerance induction (23, 24). Thus, it is possible that PD-1 ligation also may be required for optimal tolerance induction (4). In any event, our data along with the overlapping yet distinct tissue expression patterns of the CTLA-4/B7 and PD-1/PD-L pathways suggest differential effects of these pathways on regulating GVHD. We have observed that blockade of the PD-1/PD-L pathway was more potent than CTLA-4/B7 blockade for GVHD acceleration and that the combined blockade of both pathways was additive in accelerating GVHD. These latter data suggest that PD-1/PD-L and CTLA-4/B7 act independently to down-regulate GVHD lethality.
A potential mechanism for the accelerated GVHD lethality caused by PD-1-/- as compared with WT cells may be that the expansion or infiltration of donor T cells into GVHD target tissues was increased by blocking PD-1/PD-L interactions. However, no increased in vitro proliferation was observed in primary MLR responses with PD-1-/- T cells. Similarly, flow cytometric analysis of splenocytes and immunohistochemical staining of GVHD target organs (spleen, liver, lung, colon, skin) did not reveal differences in the number of CD4+ or CD8+ T cells assessed days 6–8 post-BMT (data not shown), indicating that differences in donor T cell infiltration likely were not responsible for the increased GVHD lethality induced by PD-1/PD-L blockade. Consistent with the immunohistochemistry results, in preliminary studies designed to examine the proliferative effects of anti-PD-1 mAb on donor T cells early post-BMT, the proportion of donor CD4+ and CD8+ T cells in the spleen or in the lymph node that had undergone 0–1 cell divisions, as measured by CFSE staining, was comparable in recipients treated with anti-PD-1 as compared with irrelevant mAb (n = 3/group) when assessed on day 3 post-BMT (data not shown). Thus, the marked acceleration in GVHD lethality induced by anti-PD-1 mAb does not appear to be due to a pronounced effect of PD-1/PD-L blockade on T cell proliferation.
Anti-PD-1 mAb accelerated GVHD lethality independently of FasL or perforin expression. As PD-1 ligation has been shown to decrease cytokine production in in vitro assays (11), we considered the possibility that the induction of inflammatory cytokine cascades may have been the responsible effector mechanism for the augmented GVHD lethality observed after PD-1/PD-L blockade. We observed an increase in IFN- production in MLR supernatants derived from PD-1-/- T cells. Systemic IFN- levels were augmented by PD-1/PD-L blockade and the accelerated GVHD lethality observed under these conditions was dependent on donor IFN- production. The role of IFN- levels in regulating GVHD has not been entirely resolved; sustained high IFN- production can result in more severe GVHD in some models (19, 25). However, the link between high IFN- and worse GVHD is not a universal finding, with some studies showing reduced GVHD associated with increased donor T cell apoptosis (20, 26, 27). Therefore, any propensity toward an increased division rate that might occur when the PD-1/PD-L pathway is blocked may be offset by an increased apoptosis rate caused by IFN- elevation. Early post-BMT, the dominant effect of IFN- may be the up-regulation of cell surface determinants (e.g., PD-L1 or PD-L2), host MHC or costimulatory molecules, or stimulation of host production of other inflammatory cytokines that function as GVHD effector mechanism (e.g., TNF- or IL-1), as recently implicated by Reddy et al. (20). Serum TNF- levels were significantly elevated in anti-PD-1 vs irrelevant mAb-treated recipients on day 6 post-BMT. The regulation of systemic IFN- production by the PD-1/PD-L pathway in our GVHD setting is consistent with the reduction in cardiac graft IFN- associated with the infusion of PD-L1.Fc which appears to have resulted in PD-1 ligation (22). Taken together, we conclude that the PD-1/PD-L pathway is a major regulator of IFN- production in vivo, a finding that has implications for the biological role of this pathway in IFN--responsive diseases.
In summary, the major finding of this study is that the PD-1 pathway is a negative regulator of both CD4+ and CD8+ T cell alloresponses. This conclusion was derived from three distinct approaches used to block the PD-1 pathway: PD-L1.Fc; anti-PD-1 mAb; and PD-1-/- donor cells. PD-1 pathway blockade was associated with a heightened release of proinflammatory cytokines, particularly IFN-, that likely contributed to GVHD lethality and was not dependent perforin/FasL-mediated cytolysis. Our data provide definitive evidence that PD-1 engagement diminishes alloreactive T cell responses after BMT. These data have important implications for our understanding of T cell alloresponse and GVHD pathophysiology. Ligation of the PD-1 receptor may represent a novel approach for preventing GVHD.
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Acknowledgments |
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Footnotes |
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2 B.R.B. and B.M.C. contributed equally to this work and are listed in alphabetical order.
3 Address correspondence and reprint requests to Dr. Bruce R. Blazar, University of Minnesota, 460F CCRB, 425 East River Road, Minneapolis, MN 55455. E-mail address: blaza001{at}tc.umn.edu
4 Abbreviations used in this paper: PD-1, programmed death-1; BM, bone marrow; BMT, bone marrow transplantation; GVHD, graft-vs-host disease; FasL, Fas ligand; PD-L1, programmed death-1 ligand-1; PD-L2, programmed death-1 ligand-2; WT, wild type.
Received for publication March 6, 2003. Accepted for publication May 30, 2003.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-4 in acute graft-versus-host disease after allogeneic bone marrow transplantation in mice. J. Clin. Invest. 102:1742.[Medline]
on CD4+ T cell-mediated graft-vs-host disease: effects of conditioning. Biol. Blood Marrow Transplant. 6:605.
is required for inhibition of acute graft-versus-host disease by interleukin 12. J. Clin. Invest. 102:2126.[Medline]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
, PD-1 knockout (KO; PD-1-/-); 
, WT. B, IFN-