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CD4+ and CD8+ CD28 null T Cells Are Cytotoxic to Autologous Muscle Cells in Patients With Polymyositis
Author(s) -
Pandya Jayesh M.,
Venalis Paulius,
AlKhalili Lubna,
Shahadat Hossain Mohammad,
Stache Vanessa,
Lundberg Ingrid E.,
Malmström Vivianne,
Fasth Andreas E. R.
Publication year - 2016
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.39650
Subject(s) - cytotoxic t cell , cd28 , perforin , interleukin 21 , cd8 , t cell , biology , granzyme , microbiology and biotechnology , cancer research , immunology , antigen , immune system , in vitro , biochemistry
Objective 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. Methods 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. Results 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. Conclusion 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.