RNA-Binding Protein PCBP1/hnRNP E1 is an Intracellular Checkpoint for Shaping Effector Versus Regulatory T Cells in Immunity and Cancer

Distinct lineages of T cells can act in response to various environmental cues to either drive or restrict immune-mediated pathology. Immunotherapy involving the block of cell surface immune checkpoints CTLA-4 and PD-1/PD-L1 has revolutionized treatment of several cancers. However, additional immune regulatory mechanisms remain to be discovered, and will facilitate development of next generation agents to overcome resistance to current therapies. Here, we identify the RNA-binding protein poly(C)-binding protein 1 (PCBP1) as an intracellular checkpoint that is upregulated in activated T cells to suppress expression of effector T cell-intrinsic regulatory T (Treg) cell-commitment programs. This is critical for stabilizing effector T cell functions and subverting immune-suppressive signals. T cell-specific deletion of Pcbp1 increased Treg development, enlisted multiple inhibitory checkpoint molecules including PD-1, TIGIT and VISTA on TILs, and thwarted anti-tumor immunity. Our results demonstrate a critical role for PCBP1 as an intracellular checkpoint for balancing effector versus regulatory T cells.