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Inflammatory T cells maintain a healing disposition

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Science Immunology  04 Jan 2019:
Vol. 4, Issue 31, eaav9723
DOI: 10.1126/sciimmunol.aav9723

Abstract

Commensal-specific T cells dually possess type-2 and type-17 effector potential, allowing plasticity in orchestrating tissue immunity.

Barrier organs protect against external insults and systemic infection, but rapid repair mechanisms are required to maintain their functional integrity. A large number of resident T cells patrolling these tissues are specific for commensal antigens; however, it remains unclear how induction of microbiota-specific immune responses intersects with tissue repair pathways. This was the central question addressed by Harrison et al. By tracking CD8+ T cells specific for the skin commensal bacteria Staphylococcus epidermidis, they functionally dissected the responses of these cells in skin.

Finding that these antigen-specific CD8s are largely tissue resident memory (Trm) cells, the authors focused on comparing the effector response of RORγt+CCR6+ T cytotoxic (Tc) 17 cells, canonically known for interleukin (IL)–17 production, with that of T-bet+RORγt interferon (IFN)–γ producing Tc1s. Surprisingly, upon skin injury Tc17s, but not Tc1s, expressed the tissue repair–associated type-2 cytokines IL-5 and IL-13. The Tc17s were also positive for GATA-3, which is a lineage-defining transcription factor and regulator of type-2 immunity. Correspondingly, skin regulatory T cells were highly enriched for GATA binding protein 3 (GATA-3), and in skin of mice where GATA-3 was selectively deleted in Tregs, Tc17s expressing IL-5 and IL-13 were found in higher abundance. Assay for transposase-accessible chromatin (ATAC) and RNA sequencing of S. epidermidis–specific Tc17 and Tc1 cells revealed that the Tc17s maintained an open chromatin profile in several type-2 signature genes and expressed messenger RNA (mRNA) for IL-5 and IL-13 (although not protein) at steady state. IL-5 and IL-13 protein expression was readily inducible by either in vitro or in vivo stimulation with alarmin cytokines, so the authors concluded that S. epidermidis–specific Tc17s maintain a poised type-2 transcriptome that is activatable upon tissue injury. To demonstrate that type-2 cytokine production from Tc17s has functional importance in tissue repair, the authors utilized a skin-wounding model. S. epidermidis colonization improved wound healing in an IL-13–dependent manner, and adoptive transfer of S. epidermidis–specific CD8+ T cells into IL13-deficient mice rescued the response. Taken together, Harrison et al. have elucidated an eloquent mechanism whereby microbiota-specific T cells patrolling barrier tissues can simultaneously provide homeostatic type-17 mediated immunity and maintain readiness for participation in tissue repair responses.

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