KLF2 regulates CD8 T cell differentiation and migration in infection and cancer 2254075

Abstract

Besides acute infection, CX3CR1+ effector-like CD8 T cells also appear in chronic infection and cancer. Whether there is a central transcriptional regulator of the effector fate is unclear. Here, using joint single-cell profiling of the transcriptome and epigenome of chimeric antigen receptor (CAR) T cells, we identified KLF2 as a hub transcription factor in the gene regulatory network of effector-like CAR T cells. KLF2 deficiency abolished effector-like differentiation in both CAR T cells and antiviral CD8 T cells. KLF2 deficiency also impaired the differentiation of the stem-like subset. In both chronic viral infection and cancer, KLF2 deficiency impaired CD8 T cell infiltration to non-lymphoid tissues. However, unlike CAR T cells, KLF2-deficient antiviral CD8 T cells showed a greater expansion in the lymphoid tissue. Single-cell transcriptomics analysis revealed that KLF2-deficient CD8 T cells upregulated the transcriptional signature of terminally exhausted T cells and downregulated the signature of effector-like T cells, suggesting a central role of KLF2 in regulating the bifurcation of effector versus terminal exhaustion cell fates. In addition, the TOX-controlled transcriptional program was upregulated in KLF2-deficient CD8 T cells. KLF2 deficiency downregulated multiple genes associated with T cell migration including S1pr1. S1PR1 deficiency impaired the effector-like subset, whereas deficiency of CD69, a negative regulator of S1PR1, increased the effector-like subset. Notably, aging downregulated KLF2 in antigen-specific CD8 T cells, impaired the differentiation of the CX3CR1+ subset, and upregulated the TOX-mediated transcriptional program. Thus, our study demonstrates KLF2 as a central regulator of the effector fate and migration of CD8 T cells. NIH, CRI, AFAR, V Foundation Immune Response Regulation: Molecular Mechanisms (IRM)