T Cell Infiltrates in the Muscles of Patients with Dermatomyositis and Polymyositis Are Dominated by CD28null T Cells

Abstract

Dermatomyositis and polymyositis are disabling rheumatic diseases characterized by an appreciable number of T cells infiltrating muscle tissue. The precise phenotype, function and specificity of these cells remain elusive. In this study, we aimed to characterize T cells in muscle tissue and circulation and to investigate their association to clinical phenotype. Twenty-four patients with dermatomyositis and 42 with polymyositis were screened for frequency of CD4+CD28null and CD8+CD28null T cells in peripheral blood by flow cytometry. Presence of these cells in inflamed muscle tissue from 13 of these patients was analyzed by three-color immunofluorescence microscopy. Effector functions, proliferation and Ag specificity were analyzed by flow cytometry after in vitro stimulation. The clinical relevance of CD28null T cells was analyzed by multiple regression analyses including six separate and combined disease variables. We demonstrate that muscle-infiltrating T cells are predominantly CD4+CD28null and CD8+CD28null T cells in patients with dermatomyositis and polymyositis. Muscle-infiltrating CD28null T cells were found already at time of diagnosis. Disease activity correlated with the frequency of CD8+ T cells in the inflamed muscles of polymyositis patients. Circulating CD4+CD28null and CD8+CD28null T cells were significantly more frequent in human CMV (HCMV) seropositive individuals, responded to HCMV Ag stimulation, and correlated with disease duration. These cells also display a proinflammatory cytokine profile, contain perforin and lack the costimulatory molecule CD28. Our observations imply that CD28null T cells represent clinically important effector cells in dermatomyositis and polymyositis, and that HCMV might play a role in propagating disease in a subset of patients.

Activating NK‐cell receptors co‐stimulate CD4+CD28− T cells in patients with rheumatoid arthritis

“…Patients with chronic inflammatory disorders such as rheumatoid arthritis (RA), multiple sclerosis, and idiopathic inflammatory myopathies often display increased frequencies of highly differentiated effector CD4 1 CD28 À T cells in peripheral blood as compared with healthy controls [1][2][3]. These T cells are proinflammatory, cytotoxic, and may contribute to disease manifestations [4,5].…”

“…These T cells are proinflammatory, cytotoxic, and may contribute to disease manifestations [4,5]. Indeed, in a number of diseases CD4 1 CD28 À T cells have been shown to infiltrate into the main target organ and their presence mirrors disease activity [3,6,7]. Typical characteristics of CD4 1 CD28 À T cells are a restricted TCR repertoire, rapid secretion of IFN-g and TNF, cytotoxic activity, and CD57 expression indicative of a highly differentiated phenotype [8][9][10].…”

Immune and myodegenerative pathomechanisms in inclusion body myositis

“…Short‐telomer‐bearing CD8 + CD28 − T cells are thought to comprise a highly differentiated oligoclonal subset arising from chronic antigen exposure as hypothesized for IBM19, 49, 73, 74, 75, 76, 77 and several autoimmune conditions are accompanied by increased frequencies of CD8 + CD28 − T cells 78, 79, 80. Furthermore, muscle‐infiltrating CD8 + T cells in patients suffering from PM and DM have been reported to be mainly CD28 − 81. Two recent studies showed that frequencies of highly cytotoxic CD8 + CD28 − T cells in inflamed muscle and in peripheral blood of IBM patients are significantly increased and their capability to secrete IFN γ was superior compared to healthy controls 82, 83.…”

Immunotherapies for Immune-Mediated Myopathies: A Current Perspective

“…These cells putatively induce cytotoxic myonecrosis through an interaction between antigen-presenting MHC-I molecules and co-stimulatory molecules on CD8+ cells [6,17,18]. The infiltrating cells in PM also include CD68+ macrophages and myeloid dendritic cells, which are thought to participate in the cytotoxic process [2,19], as well as apoptosis-resistant CD8+CD28−/−, CD4+ CD28−/−, cells which have been suggested may contribute to treatment resistance [20]. T-cell receptor profiling has shown that the CD8+ T cells are clonally restricted in situ and persist over time [21][22][23].…”