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- Title
CD4+ and CD8+ CD28<sup>null</sup> T Cells Are Cytotoxic to Autologous Muscle Cells in Patients With Polymyositis.
- Authors
Pandya, Jayesh M.; Venalis, Paulius; Al‐Khalili, Lubna; Shahadat Hossain, Mohammad; Stache, Vanessa; Lundberg, Ingrid E.; Malmström, Vivianne; Fasth, Andreas E. R.
- Abstract
Objective Inflammatory T cell infiltrates in the skeletal muscle tissue of patients with polymyositis are dominated by CD28-negative effector (CD28null) 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 CD28null 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+CD28null and CD8+CD28null 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+ CD28null 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 CD28null 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+ CD28null 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 CD28null T cells are key effector cells that contribute to the muscle cell damage in polymyositis.
- Subjects
APOPTOSIS; BIOPSY; CELL culture; FLOW cytometry; FLUORESCENT antibody technique; GENE expression; MICROSCOPY; POLYMYOSITIS; RESEARCH funding; STATISTICS; T cells; DATA analysis; DATA analysis software; SKELETAL muscle; CYTOTOXINS; DESCRIPTIVE statistics; IN vitro studies; MANN Whitney U Test
- Publication
Arthritis & Rheumatology, 2016, Vol 68, Issue 8, p2016
- ISSN
2326-5191
- Publication type
Article
- DOI
10.1002/art.39650