PD-L1 Expression on Retrovirus-Infected Cells Mediates Immune Escape from CD8+ T Cell Killing.
Cytotoxic CD8+ T Lymphocytes (CTL) efficiently control acute virus infections but can become exhausted when a chronic infection develops. Signaling of the inhibitory receptor PD-1 is an important mechanism for the development of virus-specific CD8+ T cell dysfunction. However, it has recently been shown that during the initial phase of infection virus-specific CD8+ T cells express high levels of PD-1, but are fully competent in producing cytokines and killing virus-infected target cells. To better understand the role of the PD-1 signaling pathway in CD8+ T cell cytotoxicity during acute viral infections we analyzed the expression of the ligand on retrovirus-infected cells targeted by CTLs. We observed increased levels of PD-L1 expression after infection of cells with the murine Friend retrovirus (FV) or with HIV. In FV infected mice, virus-specific CTLs efficiently eliminated infected target cells that expressed low levels of PD-L1 or that were deficient for PD-L1 but the population of PD-L1high cells escaped elimination and formed a reservoir for chronic FV replication. Infected cells with high PD-L1 expression mediated a negative feedback on CD8+ T cells and inhibited their expansion and cytotoxic functions. These findings provide evidence for a novel immune escape mechanism during acute retroviral infection based on PD-L1 expression levels on virus infected target cells.
Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Ilseyar
I
Akhmetzyanova
Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Malgorzata
M
Drabczyk
University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America.
C Preston
CP
Neff
Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Kathrin
K
Gibbert
Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Kirsten K
KK
Dietze
Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Tanja
T
Werner
Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; Department of Infectious Diseases, Union Hospital of Tonji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
Jia
J
Liu
Department of Immunobiology, Yale School of Medicine, Yale University, New Haven, Connecticut, United States of America.
Lieping
L
Chen
Institute for Immunology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Karl S
KS
Lang
University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America.
Brent E
BE
Palmer
Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Ulf
U
Dittmer
Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Gennadiy
G
Zelinskyy
D000818:Animals; D060890:B7-H1 Antigen / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D012190:Retroviridae / Q000276:immunology; D012192:Retroviridae Infections / Q000276:immunology*
D060890:B7-H1 Antigen; D061026:Programmed Cell Death 1 Receptor