CX(3)CR1 drives cytotoxic CD4(+)CD28(-) T cells into the brain of multiple sclerosis patients

J Autoimmun. 2012 Feb;38(1):10-9. doi: 10.1016/j.jaut.2011.11.006. Epub 2011 Nov 26.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / metabolism
  • Brain / immunology*
  • Brain / metabolism
  • Brain / pathology
  • CD28 Antigens / immunology
  • CD28 Antigens / metabolism
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CX3C Chemokine Receptor 1
  • Cell Movement / immunology
  • Cells, Cultured
  • Chemokine CX3CL1 / cerebrospinal fluid
  • Chemokine CX3CL1 / immunology
  • Chemokine CX3CL1 / metabolism
  • Female
  • Flow Cytometry
  • Humans
  • Immunohistochemistry
  • Immunologic Memory / immunology
  • Immunophenotyping
  • Male
  • Middle Aged
  • Multiple Sclerosis / immunology*
  • Multiple Sclerosis / metabolism
  • Receptors, Chemokine / immunology*
  • Receptors, Chemokine / metabolism
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism
  • Young Adult


  • CD28 Antigens
  • CX3C Chemokine Receptor 1
  • CX3CR1 protein, human
  • Chemokine CX3CL1
  • Receptors, Chemokine