TY - JOUR
T1 - UFL1 promotes survival and function of virtual memory CD8 T cells
AU - Bhatt, Brinda
AU - Kumar, Kunal
AU - Shi, Huidong
AU - Ganesan, Dhasarathan
AU - Anazodo, Francis
AU - Rathakrishnan, Aravind
AU - Zhu, Huabin
AU - Wanna, Andrew
AU - Jiang, Chen
AU - Jayavelu, Tamilselvan
AU - Lokeshwar, Vinata Bal
AU - Pacholczyk, Rafal
AU - Munn, David H.
AU - Sheridan, Brian S.
AU - Moskophidis, Demetrius
AU - Li, Honglin
AU - Singh, Nagendra
N1 - Publisher Copyright:
© The Author(s) 2025. Published by Oxford University Press on behalf of The American Association of Immunologists. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please
PY - 2025/3/1
Y1 - 2025/3/1
N2 - In naïve mice, a fraction of CD8 T cells displaying high affinity for self-MHC peptide complexes develop into virtual memory T (TVM) cells. Due to self-reactivity, TVM cells are exposed to persistent antigenic stimulation, a condition known to induce T cell exhaustion. However, TVM cells do not exhibit characteristics similar to exhausted CD8 T (TEX) cells. Here, we tested the role of the UFL1, E3 ligase of the ufmylation pathway in TVM cells. We show that UFL1 prevents the acquisition of epigenetic, transcriptional, and phenotypic changes in TVM cells that are similar to TEX cells and thus promote their survival and function. UFL1-deficient TVM cells failed to protect mice against Listeria infection. Epigenetic analysis showed higher BATF activity in UFL1-deficient TVM cells. Deletion of BATF and not PD1 decreased inhibitory molecules expression and restored the survival and function of UFL1-deficient TVM cells. Our findings demonstrate a key role of UFL1 in inhibiting the exhaustion of TVM cells and promoting their survival and function.
AB - In naïve mice, a fraction of CD8 T cells displaying high affinity for self-MHC peptide complexes develop into virtual memory T (TVM) cells. Due to self-reactivity, TVM cells are exposed to persistent antigenic stimulation, a condition known to induce T cell exhaustion. However, TVM cells do not exhibit characteristics similar to exhausted CD8 T (TEX) cells. Here, we tested the role of the UFL1, E3 ligase of the ufmylation pathway in TVM cells. We show that UFL1 prevents the acquisition of epigenetic, transcriptional, and phenotypic changes in TVM cells that are similar to TEX cells and thus promote their survival and function. UFL1-deficient TVM cells failed to protect mice against Listeria infection. Epigenetic analysis showed higher BATF activity in UFL1-deficient TVM cells. Deletion of BATF and not PD1 decreased inhibitory molecules expression and restored the survival and function of UFL1-deficient TVM cells. Our findings demonstrate a key role of UFL1 in inhibiting the exhaustion of TVM cells and promoting their survival and function.
KW - UFL1
KW - exhaustion
KW - memory
KW - virtual memory T cell
UR - https://www.scopus.com/pages/publications/105010002701
U2 - 10.1093/jimmun/vkae042
DO - 10.1093/jimmun/vkae042
M3 - Article
C2 - 40073095
AN - SCOPUS:105010002701
SN - 0022-1767
VL - 214
SP - 446
EP - 459
JO - Journal of Immunology
JF - Journal of Immunology
IS - 3
ER -