Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 Jul;120(7):2508-15.
doi: 10.1172/JCI40040. Epub 2010 Jun 14.

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

Scott N Mueller  1 , Vijay K Vanguri, Sang-Jun Ha, Erin E West, Mary E Keir, Jonathan N Glickman, Arlene H Sharpe, Rafi Ahmed
Affiliations

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

Scott N Mueller et al. J Clin Invest. 2010 Jul.

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1. PD-L1 expression on hematopoietic cells inhibits virus-specific CD8+ T cell responses.
(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.
Figure 2
Figure 2. PD-L1 expression on hematopoietic cells influences CTL function.
(A) IFN-γ and TNF-α production by GP33- and GP276-specific CD8+ T cells in the spleen 8 days after infection. Numbers in the upper quadrants represent the proportion of total CD8+ T cells expressing IFN-γ (left) or IFN-γ and TNF-α (right) after GP33 or GP276 stimulation. (B) The number of IFN-γ+ and (C) IFN-γ+TNF-α+ cells responding to NP396, GP33, GP276, GP118, and NP235 epitopes. n = 4–8 mice per group. Mean + SEM of data from 1 of 4 representative experiments are shown.
Figure 3
Figure 3. PD-L1 expression on hematopoietic cells controls CD8+ and CD4+ T cell responses in lymphoid and nonlymphoid tissues.
(A) GP33- and GP276-specific responses in the liver and lungs 8 days after CL-13 infection were measured using MHC class I tetramers. (B) The number of CD8+ IFN-γ+ cells responding to 6 LCMV epitopes (GP33, GP276, NP396, NP235, NP205, and GP118) in the spleen, liver, and lung 8 days after infection. Responses to individual epitopes were obtained for each sample and then pooled for display. (C) The number of CD4+IFN-γ+GP61–specific T cells in the spleen, liver, and lungs 8 days after LCMV CL-13 infection. n = 3–4 mice per group. Mean + SEM of data from 1 of 3 representative experiments are shown. *P < 0.05; **P = 0.01; ***P < 0.005.
Figure 4
Figure 4. PD-L1 expression on nonhematopoietic cells influences viral clearance.
Viral titers in the blood (serum), spleen, liver, and lungs 8 days after LCMV CL-13 infection. n = 3–4 mice per group. Mean + SEM of data from 1 of 4 representative experiments are shown. *P ≤ 0.05; **P ≤ 0.005; ***P < 0.0001.
Figure 5
Figure 5. PD-L1 expression on nonhematopoietic cells influences survival and immunopathology after infection.
(A) Chimeric mice were infected with LCMV CL-13 and survival monitored daily. n = 7–10 mice; 1 representative experiment of 3 is shown. (B) Severe pathology in the BM compartment in chimeric mice lacking PD-L1 on nonhematopoietic cells. Representative photomicrographs of BM from CL-13–infected chimeric mice 8 days after infection. Pdl1–/– mice reconstituted with WT or Pdl1–/– BM (P-P or W-P) demonstrated significant necrosis of the BM compartment in contrast with W-W and P-W groups, which did not show necrosis. Original magnification, ×400.
Figure 6
Figure 6. Model comparing roles of hematopoietic and nonhematopoietic cells in regulating T cell responses via the PD-1/PD-L1 pathway during infection.
(A) BM-derived cells, such as APCs, upregulate PD-L1 after infection and interact with PD-1+ antigen–specific T cells, negatively regulating cell expansion and cytokine production. Interactions between CD28 on T cells and B7 (CD80 or CD86) on APC costimulates antigen-specific TCR-MHC interactions and can be inhibited by concurrent PD-1/PD-L1 interactions. PD-L1 on T cells may also interact with CD80 on APCs to deliver inhibitory signals (not shown). (B) PD-L1 is upregulated on infected nonhematopoietic cells in tissues and regulates viral clearance and immunopathology during infection.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Barber DL, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439(7077):682–687. doi: 10.1038/nature04444. - DOI - PubMed
    1. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8(3):239–245. doi: 10.1038/ni1443. - DOI - PubMed
    1. Mueller SN, et al. Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection. Proc Natl Acad Sci U S A. 2007;104(39):15430–15435. doi: 10.1073/pnas.0702579104. - DOI - PMC - PubMed
    1. Probst HC, McCoy K, Okazaki T, Honjo T, van den Broek M. Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nat Immunol. 2005;6(3):280–286. doi: 10.1038/ni1165. - DOI - PubMed
    1. Tsushima F, et al. Interaction between B7-H1 and PD-1 determines initiation and reversal of T-cell anergy. Blood. 2007;110(1):180–185. doi: 10.1182/blood-2006-11-060087. - DOI - PMC - PubMed

Publication types