CD4+CD28null T cells in autoimmune disease: Pathogenic features and decreased susceptibility to immunoregulation

Abstract

CD4+CD28null T cells have been described to be generated as a consequence of persistent immune stimulation. These CD4+ T cells are incapable of providing help for B cell proliferation and antibody production, but have acquired cytolytic function. To date, the triggers of activation of CD4+CD28null T cells have not been fully elucidated. An expansion of this cell subset has been described in several pathological conditions including multiple sclerosis (MS) and rheumatoid arthritis (RA). In this study the role of the expanded CD4+CD28null T cell subset in RA and MS pathology was further investigated. CD4+CD28null T cells were found to be terminally differentiated effector memory cells. They are equipped to infiltrate tissues and could be detected in the synovial tissue of RA patients. Whereas no reactivity to candidate autoantigens (myelin, collagen) was observed within the CD4+CD28null T cell subset, cytomegalovirus (CMV) reactivity was prominent in 4/4 HC, 4/4 RA patients and 3/4 MS patients. Of note was that the intensity of the CMV induced proliferative response was related to the number of CMV epitopes recognized. Interestingly, our results illustrated that CD4+CD28null T cells were not susceptible to the suppressive actions of CD4+CD25high regulatory T cells. In conclusion, this study provides several indications for a role of CD4+CD28null T cells in autoimmune pathology. These cells display pathogenic features, fill up immunological space and are less vulnerable to regulatory mechanisms. However, our results do not support a direct autoreactive role of CD4+CD28null T cells in the pathogenesis of autoimmune diseases.