Work

Genetic absence of PD-L1 does not restore CD8 + T cell function during respiratory virus infection and delays virus clearance

Year: 2024

Type: article

Abstract: ABSTRACT A key mediator of T cell impairment during respiratory virus infection is the inhibitory receptor PD-1. PD-1 is induced on T cells following antigen exposure, whereas proinflammatory cytokines upregulate the ligands PD-L1 and PD-L2. Respiratory virus infection leads to upregulation of PD-L1 on airway epithelial cells, dendritic cells, and alveolar macrophages. However, the role of PD-L1 on different cell types in acute respiratory virus infections is not known. We sought to determine the role of PD-L1 on different cell types in CD8 + T cell impairment. We found that PD-L1 −/− mice challenged with human metapneumovirus or influenza showed a similar level of CD8 + T cell impairment compared to wild-type (WT) mice. Moreover, virus clearance was delayed in PD-L1 −/− mice compared to WT. CD8 + T cells from PD-L1-deficient mice expressed higher levels of inhibitory receptors both at baseline and after respiratory virus infection. The antibody blockade of PD-L2 failed to restore function to the impaired cells. While reciprocal bone marrow chimeras between WT and PD-L1 −/− mice did not restore CD8 + T cell function after the respiratory virus challenge, mice that received the PD-L1 −/− bone marrow had higher inhibitory receptor expression on CD8 + cells. This discrepancy in the inhibitory receptor expression suggests that cells of the hematopoietic compartment contribute to T cell impairment on CD8 + T cells. IMPORTANCE The phenomenon of pulmonary CD8 + T cell impairment with diminished antiviral function occurs during acute respiratory virus infection mediated by Programmed Cell Death-1 (PD-1) signaling. Moreover, PD-1 blockade enhances T cell function to hasten viral clearance. The ligand PD-L1 is expressed in many cell types, but which cells drive lung T cell impairment is not known. We used genetic approaches to determine the contribution of PD-L1 on lung T cell impairment. We found that PD-L2 cannot compensate for the loss of PD-L1, and PD-L1-deficient mice exhibit increased expression of other inhibitory receptors. Bone marrow chimeras between PD-L1-deficient and wild-type mice indicated that hematopoietic PD-L1 expression is associated with inhibitory receptor upregulation and impairment.

Source: Journal of Virology

DOI: 10.1128/jvi.00797-24

Authors: Meredith C. Rogers, Kristina D. Lamens, Sharon J. Tollefson, John V. Williams

Institutions: University of Pittsburgh, Vanderbilt University, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Vanderbilt University Medical Center

Language: English

Topic: T-cell and B-cell Immunology

Subfield: Immunology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green