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CD4⁺CD28^null T Cells in Autoimmune Disease: Pathogenic Features and Decreased Susceptibility to Immunoregulation¹

Marielle Thewissen^*, Veerle Somers^*, Niels Hellings^*, Judith Fraussen^*, Jan Damoiseaux and Piet Stinissen^2,*

^* Hasselt University, Biomedical Research Institute, and School of Life Sciences, Transnationale Universiteit Limburg, Diepenbeek, Belgium; and Department of Clinical and Experimental Immunology, University Hospital Maastricht, Maastricht, The Netherlands

To determine the role of expanded CD4⁺CD28^null T cells in multiple sclerosis and rheumatoid arthritis pathology, these cells were phenotypically characterized and their Ag reactivity was studied. FACS analysis confirmed that CD4⁺CD28^null T cells are terminally differentiated effector memory cells. In addition, they express phenotypic markers that indicate their capacity to infiltrate into tissues and cause tissue damage. Whereas no reactivity to the candidate autoantigens myelin basic protein and collagen type II was observed within the CD4⁺CD28^null T cell subset, CMV reactivity was prominent in four of four HC, four of four rheumatoid arthritis patients, and three of four multiple sclerosis patients. The level of the CMV-induced proliferative response was found to be related to the clonal diversity of the response. Interestingly, our results illustrate that CD4⁺CD28^null T cells are not susceptible to the suppressive actions of CD4⁺CD25⁺ regulatory T cells. In conclusion, this study provides several indications for a role of CD4⁺CD28^null T cells in autoimmune pathology. CD4⁺CD28^null T cells display pathogenic features, fill up immunological space, and are less susceptible to regulatory mechanisms. However, based on their low reactivity to the autoantigens tested in this study, CD4⁺CD28^null T cells most likely do not play a direct autoaggressive role in autoimmune disease.

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 Hasselt University and the Transnationale Universiteit Limburg.

² Address correspondence and reprint requests to Dr. Piet Stinissen, Hasselt University, Biomedisch Onderzoeksinstituut, and School of Life Sciences, Transnationale Universiteit Limburg, Agoralaan, Building A, Diepenbeek, Belgium. E-mail address: piet.stinissen{at}uhasselt.be

³ Abbreviations used in this paper: Treg, regulatory T cell; RA, rheumatoid arthritis; MS, multiple sclerosis; HC, healthy control; SF, synovial fluid; ST, synovial tissue; SFMC, SF mononuclear cell; GrA, granzyme A; GrB, granzyme B; MBP, myelin basic protein; hCII, human collagen type II; PF, proliferating fraction; TT, tetanus toxoid; MFI, mean fluorescence intensity.

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