TY - JOUR
T1 - PD-1 Signaling Promotes Control of Chronic Viral Infection by Restricting Type-I-Interferon-Mediated Tissue Damage
AU - Raju, Saravanan
AU - Verbaro, Daniel J.
AU - Egawa, Takeshi
N1 - Funding Information:
We thank M. Colonna and M. Cella for LCMV stocks; M.S. Diamond for Ifnar1 −/− mice; J. Boon, C. Fujii, and M. Holmgren for technical support; and C.-S. Hsieh, E.M. Oltz, and E. Tonc for discussion and critical reading of the manuscript. This study was supported by United States National Institutes of Health ( NIH) grants R01AI130152-01A1 and R03AI139875-01 (to T.E.), T32HL007317 (to S.R.), and T32GM007200 (to S.R. and D.J.V.). T.E. is a Scholar of the Leukemia and Lymphoma Society ( https://www.lls.org , United States). The ORCID for T.E. is 0000-0001-7489-1051.
Funding Information:
We thank M. Colonna and M. Cella for LCMV stocks; M.S. Diamond for Ifnar1?/? mice; J. Boon, C. Fujii, and M. Holmgren for technical support; and C.-S. Hsieh, E.M. Oltz, and E. Tonc for discussion and critical reading of the manuscript. This study was supported by United States National Institutes of Health (NIH) grants R01AI130152-01A1 and R03AI139875-01 (to T.E.), T32HL007317 (to S.R.), and T32GM007200 (to S.R. and D.J.V.). T.E. is a Scholar of the Leukemia and Lymphoma Society (https://www.lls.org, United States). The ORCID for T.E. is 0000-0001-7489-1051. S.R. and T.E. designed the study. S.R. and D.J.V. conducted experiments. S.R. and T.E. interpreted results and wrote the manuscript. The authors declare no competing interests.
Publisher Copyright:
© 2019 The Author(s)
PY - 2019/11/26
Y1 - 2019/11/26
N2 - Immune responses are essential for pathogen elimination but also cause tissue damage, leading to disease or death. However, it is unclear how the host immune system balances control of infection and protection from the collateral tissue damage. Here, we show that PD-1-mediated restriction of immune responses is essential for durable control of chronic LCMV infection in mice. In contrast to responses in the chronic phase, PD-1 blockade in the subacute phase of infection paradoxically results in viral persistence. This effect is associated with damage to lymphoid architecture and subsequently decreases adaptive immune responses. Moreover, this tissue damage is type I interferon dependent, as sequential blockade of the interferon receptor and PD-1 pathways prevents immunopathology and enhances control of infection. We conclude that PD-1-mediated suppression is required as an immunoregulatory mechanism for sustained responses to chronic viral infection by antagonizing type-I interferon-dependent immunopathology.
AB - Immune responses are essential for pathogen elimination but also cause tissue damage, leading to disease or death. However, it is unclear how the host immune system balances control of infection and protection from the collateral tissue damage. Here, we show that PD-1-mediated restriction of immune responses is essential for durable control of chronic LCMV infection in mice. In contrast to responses in the chronic phase, PD-1 blockade in the subacute phase of infection paradoxically results in viral persistence. This effect is associated with damage to lymphoid architecture and subsequently decreases adaptive immune responses. Moreover, this tissue damage is type I interferon dependent, as sequential blockade of the interferon receptor and PD-1 pathways prevents immunopathology and enhances control of infection. We conclude that PD-1-mediated suppression is required as an immunoregulatory mechanism for sustained responses to chronic viral infection by antagonizing type-I interferon-dependent immunopathology.
UR - http://www.scopus.com/inward/record.url?scp=85075464028&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2019.10.092
DO - 10.1016/j.celrep.2019.10.092
M3 - Article
C2 - 31775026
AN - SCOPUS:85075464028
SN - 2211-1247
VL - 29
SP - 2556-2564.e3
JO - Cell Reports
JF - Cell Reports
IS - 9
ER -