Krüppel-like factor 4 regulates the survival and function of intestinal CD4+ tissue resident memory T cells 4394

Abstract Description Tissue resident memory T cells (Trms) are the first line of mucosal immunity and respond quickly upon pathogen re-encounter. Trms adapt to their environment but the transcription factor (TF) network controlling intestinal CD4+ Trms is not clear. Utilizing a murine oral immunization model with an attenuated E. coli Heat Labile Toxin (dmLT) we identify that dmLT-specific CD4+ T cells are long-lived within the small intestinal lamina propria (siLP). RNA sequencing of dmLT-specific CD4+ T cells revealed a transcriptional signature consistent with a Trm phenotype and that the transcription factor Krüppel-like factor 4 (KLF4) was enriched in siLP resident memory T cells. Conditional deletion of KLF4 in T cells after oral vaccination or viral infection resulted in decreased numbers of intestinal CD4+ Trms, but had no effect on T cells in the lymph nodes, spleen or lungs. T cell-specific KLF4 deficient mice also displayed decreased protection upon oral re-challenge with a recombinant L. monocytogenes expressing the immunodominant peptide of dmLT. Analysis of human and mouse scRNAseq datasets reveal that KLF4 is distinctly expressed in intestinal Trms. Transcriptional comparison of KLF4+/+ and KLF4-/- dmLT-specific CD4+ T cells revealed KLF4 regulates the expression of core Trm and metabolism genes in intestinal CD4+ T cells. Taken together we have identified that expression of KLF4 is critical for the survival and protective function of intestinal CD4+ Trm cells. Funding Sources Burroughs Wellcome PATH Award Topic Categories Mucosal and Regional Immunology (MUC)