Loss of CXCR6 in antigen-specific CD4+ Th2 cells reduces exhaustion and increases cytotoxicity in mouse models of autoimmunity and cancer

Summary: Abstract Body: CXCR6 is a key component of the tissue-residency gene program, contributing to CD8+ T cell resident memory (Trm) maintenance in tissues such as the lungs and skin in the context of melanoma. Its ligand, CXCL16, is expressed by epithelial cells under homeostatic conditions in both membrane-bound and cleaved forms. Our lab previously demonstrated that CXCR6 is highly expressed on antigen-specific CD4+ Th2-skewed cells (OT2) in a mouse model of cutaneous lupus erythematosus (CLE) and that the cognate ligand CXCL16 is expressed in lesional skin. Based on the importance of CXCR6 expression on CD8+ T cells, we hypothesized that CXCR6 expression is also important in CD4+ memory T cell generation in the skin. To test this, we injected CXCR6 KO versus WT Th2 skewed OT2 cells into CLE recipient mice. CXCR6 KO OT2 induced more severe skin lesions and greater weight loss compared to mice receiving wild-type (WT) T cells. Examination of activation markers on preinjection T cells revealed that CXCR6 KO OT2 expresses more CD127 and NKG2A/C/E. Since these CD4+ T cells seemed to be more activated and less exhausted, we hypothesized that they would be beneficial in a cancer model. To test this, we transferred activated CXCR6 KO or WT OT2 T cells into Rag1 KO mice engrafted with B16-OVA melanoma cells 10 days prior. Mice that received CXCR6KO OT2 exhibited increased survival and reduced PD-1 expression on antigen-specific CD4+ T cells compared to those receiving WT OT2 T cells. Together, these findings suggest that CXCR6 plays a critical role in CD4+ T helper cell effector function and exhaustion, and may have implications for CAR-T cell therapy. Further studies are warranted to determine how CXCR6 signaling may differ in CD4 T cells versus CD8 T cells, and the importance of the Th2 skewing protocol on this signaling pathway during CD4 T cell activation. Saeed Shakiba¹, Mridushi Daga¹, Ummugulsum Yildiz Altay¹, Jillian Richmond¹ 1. Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, United States. Adaptive and Auto-Immunity