title: FOXP3+ T Cells Recruited to Sites of Sterile Skeletal Muscle Injury Regulate the Fate of Satellite Cells and Guide Effective Tissue Regeneration.
abstract: Muscle injury induces a classical inflammatory response in which cells of the innate immune system rapidly invade the tissue. Macrophages are prominently involved in this response and required for proper healing, as they are known to be important for clearing cellular debris and supporting satellite cell differentiation. Here, we sought to assess the role of the adaptive immune system in muscle regeneration after acute damage. We show that T lymphocytes are transiently recruited into the muscle after damage and appear to exert a pro-myogenic effect on muscle repair. We observed a decrease in the cross-sectional area of regenerating myofibers after injury in Rag2-/- γ-chain-/- mice, as compared to WT controls, suggesting that T cell recruitment promotes muscle regeneration. Skeletal muscle infiltrating T lymphocytes were enriched in CD4+CD25+FOXP3+ cells. Direct exposure of muscle satellite cells to in vitro induced Treg cells effectively enhanced their expansion, and concurrently inhibited their myogenic differentiation. In vivo, the recruitment of Tregs to acutely injured muscle was limited to the time period of satellite expansion, with possibly important implications for situations in which inflammatory conditions persist, such as muscular dystrophies and inflammatory myopathies. We conclude that the adaptive immune system, in particular T regulatory cells, is critically involved in effective skeletal muscle regeneration. Thus, in addition to their well-established role as regulators of the immune/inflammatory response, T regulatory cells also regulate the activity of skeletal muscle precursor cells, and are instrumental for the proper regeneration of this tissue.
authors.affiliation: Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute & Vita-Salute San Raffaele University, Milan, Italy; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, United States of America; Joslin Diabetes Center, Boston, MA, United States of America; Howard Hughes Medical Institute, Cambridge, MA, United States of America; Harvard Stem Cell Institute, Cambridge, MA, United States of America; The Paul F. Glenn Laboratory for the Biological Mechanisms of Aging, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Castiglioni
authors.affiliation: Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute & Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Gianfranca
authors.initials: G
authors.lastname: Corna
authors.affiliation: Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute & Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Rigamonti
authors.affiliation: Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute & Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Basso
authors.affiliation: Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute & Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Vezzoli
authors.affiliation: Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute & Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Monno
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, United States of America; Joslin Diabetes Center, Boston, MA, United States of America; Howard Hughes Medical Institute, Cambridge, MA, United States of America; Harvard Stem Cell Institute, Cambridge, MA, United States of America; The Paul F. Glenn Laboratory for the Biological Mechanisms of Aging, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Albert E
authors.initials: AE
authors.lastname: Almada
authors.affiliation: Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute & Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Mondino
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, United States of America; Joslin Diabetes Center, Boston, MA, United States of America; Howard Hughes Medical Institute, Cambridge, MA, United States of America; Harvard Stem Cell Institute, Cambridge, MA, United States of America; The Paul F. Glenn Laboratory for the Biological Mechanisms of Aging, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
authors.affiliation: Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute & Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Manfredi
authors.affiliation: Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute & Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Rovere-Querini
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000293:injuries* / Q000473:pathology*; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D015703:Antigens, CD; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse