IL-2 enhances effector function but suppresses follicular localization of CD8+ T cells in chronic infection
Chen, Y.; Zhou, P.; Gubser, P. M.; Leong, Y. A.; He, J.; Wei, Y.; Makota, F. V.; Pazhouhandeh, M.; Zheng, T.; Yunis, J.; Li, Z.; Kallies, A.; Yu, D.
Show abstract
Cytotoxic CD8+ T cells, essential in combating viral infections and cancer, become dysfunctional from prolonged antigen exposure. Precursors of exhausted T (TPEX) cells are pivotal in sustaining immune responses in chronic diseases and mediating immunotherapy efficacy. They also control viral infection within B-cell follicles, facilitated by CXCR5 expression. How cytokines regulate TPEX cell fate and follicular entry is not well understood. We reveal that IL-2 treatment enhances CD8+ T cell effector functions in chronic LCMV infection but hinders CXCR5+ TPEX cell formation and infection control within B-cell follicles. Mechanistically, IL-2 suppresses TPEX cell differentiation in a STAT5 and BLIMP1-dependent manner. Using an IL-2 fusion protein targeting CD122, we shifted the differentiation towards CX3CR1+ T cells with increased effector function. Clinical observations with low-dose IL-2 in autoimmune disease confirmed IL-2s inhibitory effect on CXCR5+ TPEX cells, underscoring IL-2s crucial regulatory role and therapeutic potential in modulating TPEX and effector T cell generation.
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