Utilizing skin vaccination in mice that lack DCs expressing TGFβ-activating αV integrins (αV-ΔDC mice), Mani et al. show that formation of epidermal CD8+ resident memory T (eTRM) cells requires prior sustained exposure to αV+ DCs. Genome-wide chromatin accessibility analysis of resting CD44lo naive CD8+ T cells from wildtype vs αV-ΔDC mice revealed a pattern of TGFβ-induced epigenetic conditioning conducive to forming eTRm cells. Using LN-deficient mice or blocking lymphocyte tissue egress mapped eTRM differentiation capability to MHC class I-dependent interactions with migratory tissue-derived αV+ DCs that traffic via CCR7 to LNs, not spleen.
Contributed by Paula Hochman
Epithelial resident memory T (eTRM) cells serve as sentinels in barrier tissues to guard against previously encountered pathogens. How eTRM cells are generated has important implications for efforts to elicit their formation through vaccination or prevent it in autoimmune disease. Here, we show that during immune homeostasis, the cytokine transforming growth factor beta (TGF-beta) epigenetically conditions resting naive CD8(+) T cells and prepares them for the formation of eTRM cells in a mouse model of skin vaccination. Naive T cell conditioning occurs in lymph nodes (LNs), but not in the spleen, through major histocompatibility complex class I-dependent interactions with peripheral tissue-derived migratory dendritic cells (DCs) and depends on DC expression of TGF-beta-activating alphaV integrins. Thus, the preimmune T cell repertoire is actively conditioned for a specialized memory differentiation fate through signals restricted to LNs.
Author Info: (1) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA. Immunology Graduate Program, Harvard Medical School, Boston, MA, USA. (2) Cent
Author Info: (1) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA. Immunology Graduate Program, Harvard Medical School, Boston, MA, USA. (2) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (3) Center for Computational Biology, Flatiron Institute, New York, NY, USA. (4) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (5) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Bluebird Bio, 60 Binney Street, Cambridge, MA 02142, USA. (6) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA. (7) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (8) Immunology Graduate Program, Harvard Medical School, Boston, MA, USA. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (9) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA. (10) Benaroya Research Institute, Seattle, WA, USA. (11) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (12) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (13) Lydia Becker Institute of Immunology and Inflammation, Wellcome Trust Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health Manchester Academic Health Science Centre, University of Manchester, Manchester, UK. (14) Harvard Medical School, Boston, MA, USA. Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA. (15) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (16) Lydia Becker Institute of Immunology and Inflammation, Wellcome Trust Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health Manchester Academic Health Science Centre, University of Manchester, Manchester, UK. (17) Benaroya Research Institute, Seattle, WA, USA. (18) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (19) Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA. tmempel@mgh.harvard.edu. Harvard Medical School, Boston, MA, USA.
