Foxp3+CD4+ regulatory T (Treg) cells control most types of immune responses, influencing the activities of both innate and adaptive cell-types. Evidence is mounting that special classes of Tregs also regulate non- immunological processes in non-immunological cells ? and, as a consequence, organismal homeostasis. The best characterized example to date is a Foxp3+CD4+ population that resides in visceral adipose tissue and regulates local and systemic metabolic indices. Recently, a distinct Treg population was identified in murine skeletal muscle. Muscle Tregs are highly enriched within the local CD4+ T cell compartment, and have a distinctive T cell receptor repertoire and transcriptome. They regulate muscle regeneration in response to both acute and chronic injury, affecting the behavior of infiltrating innate cells as well as impacting muscle progenitor cells, at least in part via secretion of the growth/survival factor, Amphiregulin. An analogous population of Foxp3+CD4+ T cells has been identified in humans, enriched in patients with Duchenne muscular dystrophy. Preliminary data provide strong evidence that IL-33 controls Treg accumulation in injured skeletal muscle. For example, this cytokine is deficient in muscles of geriatric mice, as are Tregs, partially explaining the poor muscle repair characteristic of old animals; and this cytokine?s experimental supplementation coincident with injury significantly improves muscle repair/regeneration. Il-33 has an intriguing pattern of expression in muscle: primarily in fibro/adipogenic progenitor cells, often (though not always) in close association with archetypal nerve structures, such as nerve bundles and muscle spindles. The major goal of this proposed project is to elucidate the cellular and molecular interactions between Tregs and IL-33-producing cells during acute and chronic muscle injury. This goal will be addressed in the framework of three Specific Aims: 1) to paint a more precise picture of IL-33-producing cells in skeletal muscle; 2) to evaluate the functional relevance of the physical association between IL-33-producers and nerve structures in muscle, and 3) to explore the role of IL- 33 in a chronic muscle disease. Successful completion of these Aims stands to advance our understanding, and potential treatment, of several muscle pathologies ? including the reduced muscle mass, function and repair of the aged, muscular dystrophies such as Duchenne muscular dystrophy, and potentially Amyotrophic Lateral Sclerosis.

Public Health Relevance

This proposed project focuses on the function and cellular interactions of a recently discovered population of regulatory T cells that is localized in skeletal muscle, and regulates repair and regeneration after acute or chronic muscle injury. The identification of factors that promote the expansion and survival of this T cell population, or reparative factors that it produces, should deepen our understanding of and may aid our treatment of muscular dystrophies and potentially Amyotrophic Lateral Sclerosis (Lou Gehrig?s disease). There may also be applications to age-associated deficiencies in muscle mass, function and repair ? a growing health problem with our aging society.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Cellular and Molecular Immunology - B Study Section (CMIB)
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Carifi, Emily Foran
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Harvard Medical School
Schools of Medicine
United States
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Panduro, Marisella; Benoist, Christophe; Mathis, Diane (2018) Treg cells limit IFN-? production to control macrophage accrual and phenotype during skeletal muscle regeneration. Proc Natl Acad Sci U S A 115:E2585-E2593
DiSpirito, Joanna R; Zemmour, David; Ramanan, Deepshika et al. (2018) Molecular diversification of regulatory T cells in nonlymphoid tissues. Sci Immunol 3: