Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality
Asim Saha ... Laurence A. Turka, Bruce R. Blazar
Asim Saha ... Laurence A. Turka, Bruce R. Blazar
Published July 1, 2016
Citation Information: J Clin Invest. 2016;126(7):2642-2660. doi:10.1172/JCI85796.
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Categories: Research Article Transplantation

Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

Abstract

Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1–/– donors. PD-L1–deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1–/– donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell–mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD.

Authors

Asim Saha, Roddy S. O’Connor, Govindarajan Thangavelu, Scott B. Lovitch, Durga Bhavani Dandamudi, Caleph B. Wilson, Benjamin G. Vincent, Victor Tkachev, Jan M. Pawlicki, Scott N. Furlan, Leslie S. Kean, Kazutoshi Aoyama, Patricia A. Taylor, Angela Panoskaltsis-Mortari, Rocio Foncea, Parvathi Ranganathan, Steven M. Devine, Joel S. Burrill, Lili Guo, Catarina Sacristan, Nathaniel W. Snyder, Ian A. Blair, Michael C. Milone, Michael L. Dustin, James L. Riley, David A. Bernlohr, William J. Murphy, Brian T. Fife, David H. Munn, Jeffrey S. Miller, Jonathan S. Serody, Gordon J. Freeman, Arlene H. Sharpe, Laurence A. Turka, Bruce R. Blazar

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GVHD-induced PD-L1 upregulation on donor Teffs contributes to lethality....

Figure 1

GVHD-induced PD-L1 upregulation on donor Teffs contributes to lethality.

(A and B) Lethally irradiated B6 or BALB/c recipients were infused with 107 WT B6 BM cells plus 6 × 106 B6 Ly5.2 (CD45.1+) splenocytes. Mice were sacrificed on day 5 after BMT (n = 5 per group), and splenic donor CD4 and CD8 T cells were analyzed by flow cytometry for PD-1 (A) or PD-L1 (B) expression. Splenocytes of naive B6 Ly5.2 mice (n = 5) were included in the analysis. (C) T cells isolated from normal human donors (n = 3) were stimulated with anti–CD3/CD28 beads, and CD4 and CD8 T cells were stained for PD-L1 expression every 24 hours after stimulation. (A–C) Data are representative of 2 independent experiments. (D) Human PBMCs were collected from healthy volunteers and from patients after allogeneic BMT with or without GVHD at the time of collection (Supplemental Table 1). CD4 and CD8 T cells were then stained and analyzed for PD-L1 expression using the gating strategy as shown in Supplemental Figure 2A. (E) Lethally irradiated BALB/c recipients were infused with 107 WT B6 BM cells alone or with 1 × 106 WT B6 or Pdl1–/– purified T cells. Kaplan-Meier survival plot represents pooled data from 4 independent experiments (n = 31–34 per group; recipients of WT vs. Pdl1–/– donor T cells, P < 0.0001). (F) Lethally irradiated B10.BR recipients were infused with 107 WT B6 BM cells alone or with 3 × 106 WT B6 or Pdl1–/– purified T cells. Kaplan-Meier survival plot represents pooled data from 2 independent experiments (n = 16–20 per group; recipients of WT vs. Pdl1–/– donor T cells, P = 0.0047). (G) Lethally irradiated BALB/c recipients were infused with 107 WT B6 BM cells alone or with 1 × 106 WT B6, Pdl1–/–, or Pdl1–/– Pdl2–/– purified T cells. Kaplan-Meier survival plot of transplanted mice is shown (n = 8 per group; recipients of WT vs. Pdl1–/– donor T cells, P = 0.006; recipients of WT vs. Pdl1–/– Pdl2–/– donor T cells, P = 0.011). Data represent mean ± SEM (A, B, and D), and P values were calculated by 2-tailed t test (A, B, and D) or log-rank test (E–G). *P < 0.05, ***P < 0.001.