Ptpn2 and KLRG1 regulate the generation and function of tissue-resident memory CD8(+) T cells in skin

Tissue-resident memory T cells (T(RM) cells) are key elements of tissue immunity. Here, we investigated the role of the regulator of T cell receptor and cytokine signaling, Ptpn2, in the formation and function of T(RM) cells in skin. Ptpn2-deficient CD8(+) T cells displayed a marked defect in generating CD69(+) CD103(+) T(RM) cells in response to herpes simplex virus type 1 (HSV-1) skin infection. This was accompanied by a reduction in the proportion of KLRG1(−) memory precursor cells and a transcriptional bias toward terminal differentiation. Of note, forced expression of KLRG1 was sufficient to impede T(RM) cell formation. Normalizing memory precursor frequencies by transferring equal numbers of KLRG1(−) cells restored T(RM) generation, demonstrating that Ptpn2 impacted skin seeding with precursors rather than downstream T(RM) cell differentiation. Importantly, Ptpn2-deficient T(RM) cells augmented skin autoimmunity but also afforded superior protection from HSV-1 infection. Our results emphasize that KLRG1 repression is required for optimal T(RM) cell formation in skin and reveal an important role of Ptpn2 in regulating T(RM) cell functionality.