PD-L1 has distinct functions in hematopoietic and nonhematopoietic cells in regulating T cell responses during chronic infection in mice
Scott N. Mueller, … , Arlene H. Sharpe, Rafi Ahmed
Scott N. Mueller, … , Arlene H. Sharpe, Rafi Ahmed
Published June 14, 2010
Citation Information: J Clin Invest. 2010;120(7):2508-2515. https://doi.org/10.1172/JCI40040.
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Research Article Immunology

PD-L1 has distinct functions in hematopoietic and nonhematopoietic cells in regulating T cell responses during chronic infection in mice

Abstract

The inhibitory receptor programmed death 1 (PD-1) is upregulated on antigen-specific CD8+ T cells during persistent viral infections. Interaction with PD-1 ligand 1 (PD-L1) contributes to functional exhaustion of responding T cells and may limit immunopathology during infection. PD-L1 is expressed on both hematopoietic and nonhematopoietic cells in tissues. However, the exact roles of PD-L1 on hematopoietic versus nonhematopoietic cells in modulating immune responses are unclear. Here we used bone marrow chimeric mice to examine the effects of PD-L1 deficiency in hematopoietic or nonhematopoietic cells during lymphocytic choriomeningitis virus clone 13 (LCMV CL-13) infection. We found that PD-L1 expression on hematopoietic cells inhibited CD8+ T cell numbers and function after LCMV CL-13 infection. In contrast, PD-L1 expression on nonhematopoietic cells limited viral clearance and immunopathology in infected tissues. Together, these data demonstrate that there are distinct roles for PD-L1 on hematopoietic and nonhematopoietic cells in regulating CD8+ T cell responses and viral clearance during chronic viral infection.

Authors

Scott N. Mueller, Vijay K. Vanguri, Sang-Jun Ha, Erin E. West, Mary E. Keir, Jonathan N. Glickman, Arlene H. Sharpe, Rafi Ahmed

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Figure 1

PD-L1 expression on hematopoietic cells inhibits virus-specific CD8+ T cell responses.

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PD-L1 expression on hematopoietic cells inhibits virus-specific CD8+ T c...
(A) Lethally irradiated Pdl1–/– or WT mice were reconstituted with Pdl1–/– BM (P-P or P-W) or WT BM (W-P or W-W) and infected with LCMV CL-13 8 weeks later. Expression of PD-L1 on splenic hematopoietic cells was confirmed by flow cytometry. (B) GP33- and GP276-specific responses in the spleen 8 days after CL-13 infection were measured using MHC class I tetramers. Numbers above gates represent the percentage of CD8+ T cells staining positive for GP33 tetramer and PD-1. (C) The numbers of tetramer-positive cells in the spleen of chimeric mice 8 days after infection. (D) Expression of PD-1 on tetramer-positive cells from the spleen. n = 4–8 mice per group. Mean + SEM of data from 1 of 4 representative experiments are shown.