CD4+ and CD8+ CD28(null) T Cells Are Cytotoxic to Autologous Muscle Cells in Patients With Polymyositis

• Published in: Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2016-08, Vol.68 (8), p.2016-2026
• Main Authors: Pandya, Jayesh M, Venalis, Paulius, Al-Khalili, Lubna, Shahadat Hossain, Mohammad, Stache, Vanessa, Lundberg, Ingrid E, Malmström, Vivianne, Fasth, Andreas E R
• Format: Article
• Language: English
• Subjects: Acute Coronary Syndromes; Adult; Aged; Aged, 80 and over; CD28 Antigens; CD4-Positive T-Lymphocytes - physiology; CD8-Positive T-Lymphocytes - physiology; Cell Culture Techniques; Coculture Techniques; Costimulatory Molecules; Experimental Autoimmune Myositis; Humans; Immunosuppressive Treatment; Inclusion-Body Myositis; Inflammatory Myopathies; Medicin och hälsovetenskap; Middle Aged; Monoclonal-Antibody Analysis; Mononuclear-Cells; Muscle Cells; Pathogenic Features; Polymyositis - immunology; Rheumatoid-Arthritis; T-Lymphocytes - immunology
• ISSN: 2326-5191; 2326-5205; 2326-5205
• DOI: 10.1002/art.39650

Inflammatory T cell infiltrates in the skeletal muscle tissue of patients with polymyositis are dominated by CD28-negative effector (CD28(null) ) T cells of both the CD4 and CD8 lineage. These cells are potentially cytotoxic, and the aim of the present study was to develop a fully autologous cell culture system in which to investigate the functional contribution of such CD28(null) T cells to myotoxicity. In vitro cocultures of autologous skeletal muscle cells and T cell subsets obtained from 5 polymyositis patients were performed. Myotoxicity of T cells was quantified by calcein release and flow cytometric analyses. T cell degranulation was blocked with concanamycin A. Specific blocking of perforin, cytokines, and HLA was performed using antibodies. Both CD4+CD28(null) and CD8+CD28(null) T cells induced more muscle cell death than did their CD28+ counterparts. Differentiated muscle cells (myotubes) were more sensitive to T cell-mediated cell death than were their precursors (myoblasts). Both CD8+ and CD4+ CD28(null) T cells displayed perforin polarization toward muscle cells and secreted higher levels of granzyme B and interferon-γ (IFNγ) in coculture than did CD28+ T cells. The myotoxic effects of CD28(null) T cells were reduced upon the blocking of perforin, cytokines, and HLA. Addition of IFNγ or tumor necrosis factor did not induce skeletal muscle cell death in the absence of T cells; however, it did up-regulate HLA expression on muscle cells. Myotoxicity of CD4+ and CD8+ CD28(null) T cells is mediated by directed perforin-dependent killing and can be further influenced by IFNγ-induced HLA expression on muscle cells. The data suggest that CD28(null) T cells are key effector cells that contribute to the muscle cell damage in polymyositis.