TY - JOUR
T1 - Identification of a t-bethi quiescent exhausted cd8 t cell subpopulation that can differentiate into tim3+cx3cr1+ effectors and memory-like cells
AU - Raju, Saravanan
AU - Xia, Yu
AU - Daniel, Bence
AU - Yost, Kathryn E.
AU - Bradshaw, Elliot
AU - Tonc, Elena
AU - Verbaro, Daniel J.
AU - Kometani, Kohei
AU - Yokoyama, Wayne M.
AU - Kurosaki, Tomohiro
AU - Satpathy, Ansuman T.
AU - Egawa, Takeshi
N1 - Funding Information:
This work was supported by National Institutes of Health Grants R01AI130152-01A1 and R03AI139875-01 (to T.E.), T32HL00731 (to S.R.), T32GM007200 (to S.R. and D.J.V.), and K08CA230188 (A.T.S.). T.E. is a Leukemia and Lymphoma Society Scholar (1349-18). A.T.S. was supported by the Parker Institute for Cancer Immunotherapy Bridge Scholar Award, the Burroughs Wellcome Fund Career Award for Medical Scientists, and the Cancer Research Institute Technology Impact Award.
Publisher Copyright:
© 2021 by TheAmericanAssociation of Immunologists, Inc.
PY - 2021/6/15
Y1 - 2021/6/15
N2 - Persistent Ag induces a dysfunctional CD8 T cell state known as "exhaustion"characterized by PD-1 expression. Nevertheless, exhausted CD8 T cells retain functionality through continued differentiation of progenitor into effector cells. However, it remains ill-defined how CD8 T cell effector responses are sustained in situ. In this study, we show using the mouse chronic lymphocytic choriomeningitis virus infection model that CX3CR1+ CD8 T cells contain a T-bet-dependent TIM3_PD-1lo subpopulation that is distinct from the TIM3+CX3CR1+PD-1+ proliferative effector subset. The TIM3_CX3CR1+ cells are quiescent and express a low but significant level of the transcription factor TCF-1, demonstrating similarity to TCF-1hi progenitor CD8 T cells. Furthermore, following the resolution of lymphocytic choriomeningitis virus viremia, a substantial proportion of TCF-1+ memory-like CD8 T cells show evidence of CX3CR1 expression during the chronic phase of the infection. Our results suggest a subset of the CX3CR1+ exhausted population demonstrates progenitor-like features that support the generation of the CX3CR1+ effector pool from the TCF-1hi progenitors and contribute to the memory-like pool following the resolution of viremia.
AB - Persistent Ag induces a dysfunctional CD8 T cell state known as "exhaustion"characterized by PD-1 expression. Nevertheless, exhausted CD8 T cells retain functionality through continued differentiation of progenitor into effector cells. However, it remains ill-defined how CD8 T cell effector responses are sustained in situ. In this study, we show using the mouse chronic lymphocytic choriomeningitis virus infection model that CX3CR1+ CD8 T cells contain a T-bet-dependent TIM3_PD-1lo subpopulation that is distinct from the TIM3+CX3CR1+PD-1+ proliferative effector subset. The TIM3_CX3CR1+ cells are quiescent and express a low but significant level of the transcription factor TCF-1, demonstrating similarity to TCF-1hi progenitor CD8 T cells. Furthermore, following the resolution of lymphocytic choriomeningitis virus viremia, a substantial proportion of TCF-1+ memory-like CD8 T cells show evidence of CX3CR1 expression during the chronic phase of the infection. Our results suggest a subset of the CX3CR1+ exhausted population demonstrates progenitor-like features that support the generation of the CX3CR1+ effector pool from the TCF-1hi progenitors and contribute to the memory-like pool following the resolution of viremia.
UR - http://www.scopus.com/inward/record.url?scp=85108667498&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.2001348
DO - 10.4049/jimmunol.2001348
M3 - Article
C2 - 34088768
AN - SCOPUS:85108667498
SN - 0022-1767
VL - 206
SP - 2924
EP - 2936
JO - Journal of Immunology
JF - Journal of Immunology
IS - 12
ER -