IL-2 enhances effector function but suppresses follicular localization of CD8⁺T cells in chronic infection

Cytotoxic CD8⁺T cells, essential in combating viral infections and cancer, become dysfunctional from prolonged antigen exposure. Precursors of exhausted T (T_PEX) 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 T_PEXcell 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⁺T_PEXcell formation and infection control within B-cell follicles. Mechanistically, IL-2 suppresses T_PEXcell 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-2’s inhibitory effect on CXCR5⁺T_PEXcells, underscoring IL-2’s crucial regulatory role and therapeutic potential in modulating T_PEXand effector T cell generation.