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

OJ Harrison, JL Linehan, HY Shih, N Bouladoux… - Science, 2019 - science.org
Science, 2019science.org
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 …
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-17ARORγt+ 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 …
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