Dissecting transcription factor networks for tissue-resident CD8 T cell differentiation and maintenance 2255891

Abstract Introduction Tissue-resident memory (Trm/TDRM) T cells populate non-lymphoid tissues and provide a first line of defense against pathogen re-exposures. KLF2, Runx3, Hobit, and Blimp1 are transcription factors (TF) that are reported to contribute to Trm/TDRM differentiation or maintenance. Yet it is unclear what the relative importance of each TF is, and how that may vary among tissue microenvironments. Methods We used CRISPR-Cas9-mediated deletion of TFs to address CD8+ Trm/TDRM development in 15 distinct tissues following lymphocytic choreomengitis virus infection (Armstrong strain). Results We found modest contributions by Hobit with few significant changes in knockout Trm/TDRM cells. Runx3 deletion had minimal effects on Trm/TDRM establishment, however integrin expression was significantly altered, including reduced CD103 expression. Blimp1 deletion increased the proportion of recirculating memory T cells that expressed CD62L but had minimal impact on resident cells. Most notably, the loss of KLF2 promoted greater accumulation of Trm/TDRM-phenotype CD8 T cells within the liver and secondary lymphoid organs (SLOs) by seven days after infection and persisted long after antigen clearance. Trm/TDRM-phenotype memory cells expressing CD69, CD49a, and P2rX7 were particularly elevated within SLOs when KLF2 was lost. Conclusion These data indicate that the loss of KLF2 has a major influence on promoting Trm/TDRM establishment, Runx3 shapes Trm/TDRM phenotype, and Hobit and Blimp1 have fewer observable roles after LCMV infection of the parameters analyzed. A better understanding of the TF-mediated regulation of Trm/TDRM will help inform manipulation or programming of T cells for adoptive cell therapies, therapeutic depletion, and other applications. Funding Source n/a Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)