Tissue-intrinsic γδ T cells critically regulate Tissue-Resident Memory CD8 T cells

Abstract

SummaryBecause Tissue-Resident Memory T (TRM) cells contribute critically to body-surface immunoprotection and/or immunopathology in multiple settings, their regulation is biologically and clinically important. Interestingly, TRMcommonly develop in epithelia part-shaped by innate-like lymphocytes that become tissue-intrinsic during development. Here we show that polyclonal TRMcells induced by allergic contact dermatitis (ACD) interact with signature intraepidermal γδ T cells, facilitating a feedback-loop wherein TRM-derived IFNγ upregulates PD-L1 on γδ cells that can thereupon regulate PD1+TRM. Thus, TRMinduced by ACD in mice lacking either local γδ cells, or lacking a single gene (IFNγR) expressed by local γδ cells, displayed enhanced proliferative and effector potentials. Those phenotypes were associated with strikingly limited motility, reduced TRMquality. and an impaired capacity to restrain melanoma. Thus, inter-individual and tissue-specific variation in how tissue-intrinsic lymphocytes integrate with TRMmay sit upstream of variation in responses to cancer, allergens and other challenges, and may likewise underpin inflammatory pathologies repeatedly observed in γδ-deficient animals.