CX3 CR1 drives cytotoxic CD4+ CD28− T cells into the brain of multiple sclerosis patients

• Published in: Journal of autoimmunity 2011, Vol.38 (1), p.10-19
• Main Authors: Broux, Bieke, Pannemans, Kim, Zhang, Xin, Markovic-Plese, Silva, Broekmans, Tom, Eijnde, Bert O, Van Wijmeersch, Bart, Somers, Veerle, Geusens, Piet, van der Pol, Susanne, van Horssen, Jack, Stinissen, Piet, Hellings, Niels
• Format: Article
• Language: English
• Subjects: Allergy and Immunology
• ISSN: 0896-8411
• DOI: 10.1016/j.jaut.2011.11.006

Abstract Immunosenescence, or ageing of the immune system, contributes to the increased morbidity and mortality seen in the elderly population. Premature immunosenescence is shown to occur in a subgroup of patients with autoimmune diseases. One of the main characteristics of immunosenescence is the expansion of CD4+ CD28− T cells in the blood. In this study, we investigate the potential contribution of these cells to disease processes in a subgroup of multiple sclerosis (MS) and rheumatoid arthritis (RA) patients. Characterization of CD4+ CD28− T cells in patients and healthy controls reveals that they have an inflammation-seeking effector-memory T cell phenotype with cytotoxic properties, as they expel cytotoxic granules in response to a polyclonal stimulus or MS-related autoantigens. We identify CX3 CR1, the fractalkine receptor, as a selective marker to discriminate CD4+ CD28− T cells from their CD4+ CD28+ counterparts. CX3 CR1 expression enables CD4+ CD28− T cells to migrate towards a fractalkine gradient in vitro. In addition, we find increased levels of fractalkine in the cerebrospinal fluid and inflammatory lesions of MS patients. We demonstrate for the first time that CD4+ CD28− T cells accumulate in MS lesions of a subgroup of patients. Moreover, we have indications that these cells are cytotoxic in the target tissue. Overall, our findings suggest that CD4+ CD28− T cells migrate in response to a chemotactic gradient of fractalkine to sites of inflammation, where they contribute to the inflammatory processes in a subgroup of patients with MS and RA.