Loss of Programmed Death Ligand-1 Expression on Donor T Cells Lessens Acute Graft-Versus-Host Disease Lethality

Autor: Caleph B. Wilson, Jonathan S. Serody, David A. Bernlohr, Angela Panoskaltsis-Mortari, Scott B. Lovitch, Arlene H. Sharpe, Asim Saha, Patricia A. Taylor, Gordon J. Freeman, Govindarajan Thangavelu, Lili Guo, Kazutoshi Aoyama, James L. Riley, Bruce R. Blazar, William J. Murphy, Roddy S. O’Connor, David H. Munn, Ian A. Blair, Joel S. Burrill, Leslie S. Kean, Brian T. Fife, Jeffrey S. Miller, Nathaniel W. Snyder, Catarina Sacristán, Laurence A. Turka, Michael L. Dustin, Durga Bhavani Dandamudi, Rocio Foncea, Benjamin G. Vincent, Scott N. Furlan, Michael C. Milone
Rok vydání: 2015
Předmět:
Zdroj: Blood. 126:147-147
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood.v126.23.147.147
Popis: The PD-1/PD-L1 pathway plays an important role in regulation of alloimmune responses and in induction and maintenance of peripheral tolerance. Because GVHD is driven by donor T cells and PD-L1 expression can be markedly elevated on T cells during activation, we investigated the functional significance of PD-L1 expressed by donor T cells in regulating murine models of acute GVHD. PD-L1 expression was up-regulated on donor CD4 and CD8 T cells during GVHD. We considered the possibility that PD-L1 expression on activated donor T cells might inhibit GVHD by down regulating donor anti-host T cell responses, consistent with PD-L1 co-inhibitory activity when expressed on host parenchymal cells during GVHD. Surprisingly, T cell mediated GVHD lethality was markedly reduced in recipients of PD-L1-/- compared to WT donor T cells in both B6 to BALB/c model of GVHD(P Figure 1. PD-L1-/- vs. WT donor T cells lessen GVHD lethality, independent of donor Treg function. (A) Survival of BALB/c mice with WT B6 or PD-L1-/- T cells. (B) Survival of B10.BR mice with WT B6 or PD-L1-/- T cells. (C) Survival of BALB/c mice with WT B6 or PD-L1-/- T cells, or with WT B6 or PD-L1-/- CD25 depleted T cells (recipients of WT T cells vs. WT CD25-depleted T cells, P = 0.0003; recipients of PD-L1-/- T cells vs. PD-L1-/- CD25-depleted T cells, P = 0.2306; recipients of WT vs. PD-L1-/- T cells, P < 0.0001). (D) BALB/c mice transplanted with WT B6 or PD-L1-/- T cells. Mice were killed on d7 post-BMT and splenocytes were analyzed for LPAM-1, CCR9, and CXCR3 expression (not shown) on donor T cells. (E-F) BALB/c mice were transplanted with B6 Ly5.2 T cells plus PD-L1-/- T cells. Mice were killed on d3 post-BMT and splenocytes were analyzed for CTLA-4 and Lag-3 expression on donor T cells. Figure 1. PD-L1-/- vs. WT donor T cells lessen GVHD lethality, independent of donor Treg function. (A) Survival of BALB/c mice with WT B6 or PD-L1-/- T cells. (B) Survival of B10.BR mice with WT B6 or PD-L1-/- T cells. (C) Survival of BALB/c mice with WT B6 or PD-L1-/- T cells, or with WT B6 or PD-L1-/- CD25 depleted T cells (recipients of WT T cells vs. WT CD25-depleted T cells, P = 0.0003; recipients of PD-L1-/- T cells vs. PD-L1-/- CD25-depleted T cells, P = 0.2306; recipients of WT vs. PD-L1-/- T cells, P < 0.0001). (D) BALB/c mice transplanted with WT B6 or PD-L1-/- T cells. Mice were killed on d7 post-BMT and splenocytes were analyzed for LPAM-1, CCR9, and CXCR3 expression (not shown) on donor T cells. (E-F) BALB/c mice were transplanted with B6 Ly5.2 T cells plus PD-L1-/- T cells. Mice were killed on d3 post-BMT and splenocytes were analyzed for CTLA-4 and Lag-3 expression on donor T cells. Disclosures Aoyama: CHUGAI PHAMACEUTICAL CO.,LTD: Honoraria; Mochida Pharmaceutical Co.,Ltd: Honoraria; Kyowa Hakko Kirin Company,Limited: Honoraria. Milone:Novartis: Patents & Royalties, Research Funding. Miller:Coronado: Speakers Bureau; BioSciences: Speakers Bureau; Celegene: Speakers Bureau. Sharpe:Costim Pharmaceuticals: Patents & Royalties.
Databáze: OpenAIRE
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