The AICL-KLRF1 axis supports CD4-CD8 T cell communication and cytokine competence in pre-exhausted CD8+ T cells

Abstract Memory-like or precursor exhausted (Tpex) CD8+ T cells are a critical reservoir in chronic infections and cancer, yet the signals sustaining their cytokine production remain unclear. Here, we identify KLRF1 as part of a CD4–CD8 communication axis that supports cytokine production in late-differentiated human CD8+ T cells. KLRF1 is upregulated in late-differentiated CD8+ T cells, and neutralizing KLRF1 reduces TNF and IFN-γ production. Differentiated CD4+ T cells express the KLRF1 ligand AICL, and in co-culture only AICL+ - not AICL⁻ - CD4+ T cells enhance cytokine output in CD8+ T cells. Using spatial proteomics of lung adenocarcinoma and adjacent tissue, we found that CD4+ AICL+ and CD8+ KLRF1+ T cells are enriched and spatially interacting in non-tumor regions, whereas both populations are reduced within tumor tissue. Single-cell RNA-seq of tissue samples and scRNA/ATAC analyses of circulating immune cells further showed that CD8+KLRF1+ T cells display a Tpex-like transcriptional and chromatin-accessibility profile. Together, these data identify the AICL–KLRF1 axis as a CD4+–CD8+ communication pathway that supports cytokine competence in late-differentiated CD8+ T cells.