title: CX(3)CR1 drives cytotoxic CD4(+)CD28(-) T cells into the brain of multiple sclerosis patients.
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 CX(3)CR1, the fractalkine receptor, as a selective marker to discriminate CD4(+)CD28(-) T cells from their CD4(+)CD28(+) counterparts. CX(3)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.
authors: Hasselt University, Biomedical Research Institute and transnationale Universiteit Limburg, School of Life Sciences, Agoralaan, Building C, 3590 Diepenbeek, Belgium. bieke.broux@uhasselt.be
authors: Bieke
authors: B
authors: Broux
authors: Kim
authors: K
authors: Pannemans
authors: Xin
authors: X
authors: Zhang
authors: Silva
authors: S
authors: Markovic-Plese
authors: Tom
authors: T
authors: Broekmans
authors: Bert O
authors: BO
authors: Eijnde
authors: Bart
authors: B
authors: Van Wijmeersch
authors: Veerle
authors: V
authors: Somers
authors: Piet
authors: P
authors: Geusens
authors: Susanne
authors: S
authors: van der Pol
authors: Jack
authors: J
authors: van Horssen
authors: Piet
authors: P
authors: Stinissen
authors: Niels
authors: N
authors: Hellings
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism; D001921:Brain / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D054428:Chemokine CX3CL1 / Q000134:cerebrospinal fluid / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007156:Immunologic Memory / Q000276:immunology; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism; D019707:Receptors, Chemokine / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
chemical_list: D018106:CD28 Antigens; D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; D019707:Receptors, Chemokine