Lymph nodes fuel KLF2-dependent effector CD8⁺ T cell differentiation during chronic infection and checkpoint blockade

Exhausted CD8⁺ T (T_EX) cell responses are maintained by precursors of exhausted T (T_PEX) cells that possess high self-renewal and developmental potential. T_PEX cells also drive the proliferative burst of effector T cells upon therapeutic immune checkpoint blockade (ICB). However, the spatial context and signals that regulate their differentiation and function are not well defined. Here we identify developmental and functional compartmentalization of T_PEX and T_EX cells across secondary lymphoid organs during chronic infection. We show that stem-like CD62L⁺ T_PEX and effector-like CX3CR1⁺ T_EX cells constitute a distinct developmental lineage that is promoted by the lymph node (LN) microenvironment and dependent on the transcription factor KLF2. LNs act as a niche in which migratory dendritic cells provide antigen and costimulatory signals to maintain the proliferative fitness of CD62L⁺ T_PEX cells and generation of CX3CR1⁺ T_EX cells. Moreover, LNs exclusively drive the proliferative burst and systemic dissemination of CX3CR1⁺ T_EX cells during ICB. Thus, our findings identify a unique role for LNs in the maintenance of T cell differentiation and function during systemic chronic infection and ICB therapy.