Commensal-specific T cell plasticity promotes rapid tissue adaptation to injury

Commensal-specific T cells are flexible Barrier tissues, like the skin, are sites where noninvasive commensal microbes constantly interact with resident T cells. These encounters can result in commensal-specific T cell responses that promote, for example, host defense and tissue repair. Harrison et al. show that subsets of skin-resident commensal-specific interleukin-17A–producing CD4+ and CD8+ T cells have a dual nature: They coexpress transcription factors that direct antagonistic antimicrobial (type 17) and antiparasite and pro–tissue repair (type 2) programs. When skin is damaged, epithelial cell alarmins license type 17 T cells to turn on type 2 cytokines. Thus, commensal-specific type 17 T cells can direct antimicrobial activity under homeostatic conditions but rapidly turn on tissue repair in the context of injury. Science, this issue p. eaat6280 Skin-resident T cells co-opt tissue residency and cell-intrinsic flexibility to promote local immunity in response to injury. INTRODUCTION Barrier tissues are constitutive targets of environmental stressors and are home to a highly diverse microbiota. When the immune system encounters these noninvasive microbes, one possible result is the induction of cognate T cell responses that control various aspects of tissue function, including antimicrobial defense and tissue repair. Given the extraordinary number of antigens expressed by the microbiota, a substantial fraction of barrier tissue–resident T cells are expected to be commensal-specific, accumulating over time in response to successive exposure to new commensals. Because barrier tissues are defined by the constitutive coexistence of commensals and commensal-reactive lymphocytes, any understanding of tissue homeostasis, response to injury, and tissue-specific pathologies must occur in the context of this fundamental dialog. RATIONALE The skin serves as a primary interface with the environment and is consequently a constitutive target of environmental stressors mediated by physical damage or invasive pathogens. Tissue protection from these challenges relies on rapid and coordinated local responses tailored to both the microenvironment and the nature of the instigating injury. Our study explored whether commensal-specific T cells can act as tissue sentinels, allowing rapid adaptation to defined injuries, and how dysregulation of these responses may have pathogenic consequences. RESULTS Homeostatic encounters with commensal microbes promoted the induction of commensal-specific interleukin-17A (IL-17A)–producing T cells [CD4+ (TH17) and CD8+ (TC17)] that persisted as tissue-resident memory cells. Surprisingly, commensal-specific T cells were characterized by coexpression of classically antagonistic transcription factors (RORγt and GATA-3) that control the respective expression of type 17 and type 2 programs. Consequently, commensal-specific T cells displayed a hybrid chromatin landscape that underlies the coexpression of a broad type 2 transcriptome, including the type 2 effector cytokines IL-5 and IL-13. Notably, during homeostasis, RORγt+ T cells expressed type 2 cytokine mRNA without subsequent protein translation. By contrast, in the context of tissue challenges such as chitin injection or insect bites, commensal-specific RORγt+ T cells were able to produce type 2 cytokines (IL-5 and IL-13). The spontaneous release of type 2 cytokines by these cells was also observed in the context of local defects in immune regulation associated with impaired regulatory T cell function. Alarmins associated with tissue damage and inflammation, such as IL-1, IL-18, IL-25, and IL-33, were able to superimpose a type 2 effector program on both TC17 and TH17 cells in the context of T cell receptor engagement. Using an IL-17A fate-mapping strategy, we found that IL-17A–committed RORγt+ T cells and their IL-17A−RORγt+ counterparts both produced type 2 cytokines in response to tissue alarmins. Such cellular plasticity allows commensal-specific type 17 cells to promote IL-17A–mediated antimicrobial defense under homeostatic conditions, as well as tissue repair in an IL-13–dependent manner in the context of tissue injury. CONCLUSION Our work describes a tissue checkpoint that relies on the remarkable plasticity and adaptability of tissue-resident commensal-specific T cells. We propose that this feature may also have important implications in the etiology of tissue-specific inflammatory disorders. The extraordinary number of both commensal-derived antigens and T cells at barrier sites suggests that the ability of commensal-specific T cells to functionally adapt to injury may play a fundamental role in controlling tissue physiology. Poised type 2 immunity of commensal-specific T cells promotes rapid adaptation to tissue injury. Commensal-specific T cells produce IL-17A under homeostatic conditions for antimicrobial defense while harboring a poised type 2 transcriptome. Tissue injury licenses type 2 immune potential of commensal-specific type 17 T cells, thereby promoting tissue repair. Impaired immune regulation unleashes type 2 cytokine production from commensal-specific CD8+ TC17 cells. Barrier tissues are primary targets of environmental stressors and are home to the largest number of antigen-experienced lymphocytes in the body, including commensal-specific T cells. We found that skin-resident commensal-specific T cells harbor a paradoxical program characterized by a type 17 program associated with a poised type 2 state. Thus, in the context of injury and exposure to inflammatory mediators such as interleukin-18, these cells rapidly release type 2 cytokines, thereby acquiring contextual functions. Such acquisition of a type 2 effector program promotes tissue repair. Aberrant type 2 responses can also be unleashed in the context of local defects in immunoregulation. Thus, commensal-specific T cells co-opt tissue residency and cell-intrinsic flexibility as a means to promote both local immunity and tissue adaptation to injury.