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T Cell Infiltrates in the Muscles of Patients with Dermatomyositis and Polymyositis Are Dominated by CD28^null T Cells¹

Andreas E. R. Fasth^2,*, Maryam Dastmalchi^3,*, Afsar Rahbar^3,, Stina Salomonsson^*, Jayesh M. Pandya^*, Eva Lindroos^*, Inger Nennesmo, Karl-Johan Malmberg, Cecilia Söderberg-Nauclér, Christina Trollmo^*, Ingrid E. Lundberg^* and Vivianne Malmström^*

^* Rheumatology Unit, Department of Medicine, Center for Molecular Medicine, Department of Pathology, and Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

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⁺CD28^null and CD8⁺CD28^null 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 CD28^null 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⁺CD28^null and CD8⁺CD28^null T cells in patients with dermatomyositis and polymyositis. Muscle-infiltrating CD28^null 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⁺CD28^null and CD8⁺CD28^null 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 CD28^null 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant LSHB CT-2006-018661 from the European Union FP6 Project AutoCure. This research was also supported by European Community FP6 funding. This publication reflects only the author’s views. The European Community is not liable for any use that may be made of the information herein. Support for this work is also from The Swedish Research Council by Grant 2006-5507 (to V.M.), Grant (03642) K2005-74X-14045-05AK (to I.E.L.), and Grant K2007-56x-12615-10-3 (to C.S.-N.). Additional support is from The Swedish Rheumatism Association, King Gustaf V 80 Year Foundation, The Swedish Royal Academy of Sciences, Karolinska Institutet Foundation, and The Myositis Association.

² Address correspondence and reprint requests to Dr. Andreas Fasth, Rheumatology Unit, Center for Molecular Medicine L8:04, Karolinska University Hospital, S-171 76 Stockholm, Sweden. E-mail address: andreas.fasth{at}ki.se

³ M.D. and A.R. contributed equally to this work.

⁴ Abbreviations used in this paper: DC, dendritic cell; HCMV, human CMV; IE, immediate-early.