CD4+CD28null T Cells in Autoimmune Disease: Pathogenic Features and Decreased Susceptibility to Immunoregulation

Abstract

To determine the role of expanded CD4+CD28null 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+CD28null 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+CD28null 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+CD28null 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+CD28null T cells in autoimmune pathology. CD4+CD28null 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+CD28null T cells most likely do not play a direct autoaggressive role in autoimmune disease.

CX3CR1 drives cytotoxic CD4+CD28− T cells into the brain of multiple sclerosis patients

“…However, the reason for their expansion remains elusive. Studies regarding the antigen-specificity of CD4 þ CD28 À T cells have indicated that the majority of CD4 þ CD28 À T cells are CMV-reactive [64,65], and that at least part of this population proliferates in response to autoantigens [3,9,48]. In line with these reports, we found that the MS-related autoantigens MBP and MOG elicited degranulation of CD4 þ CD28 À T cells in a donor dependent manner.…”

“…In line with these reports, we found that the MS-related autoantigens MBP and MOG elicited degranulation of CD4 þ CD28 À T cells in a donor dependent manner. In addition, our previous study demonstrated that most CD4 þ CD28 À T cells of HC, MS and RA patients proliferated in response to CMV [48]. Researchers recently demonstrated that CMV-reactive CD4 þ T cells acquire distinct functional properties reminiscent of antiviral CD8 þ T cells [66].…”

“…Previously, it was reported that CD4 þ CD28 À T cells possess intracellular granules containing perforin and granzyme A and B [48]. To analyze their capacity to expel these molecules after activation, we studied the surface expression of CD107a on CD4 þ CD28 À cells upon addition of different stimuli.…”

“…Several groups have reported that at least a subpopulation of CD4 þ CD28 À T cells is autoreactive [9,48]. Therefore, antigenspecific degranulation of CD4 þ CD28 À T cells was assessed upon stimulation with MBP and MOG peptides.…”

Haplotype 4 of the multiple sclerosis-associated interleukin-7 receptor alpha gene influences the frequency of recent thymic emigrants

“…Aging of the immune system, also called immunosenescence, has been found to be accelerated in patients with a diverse range of autoimmune diseases. 25,26 Given the relatively low odds ratio (1:18) 8 of the IL-7Ra gene regarding its association to MS, a small effect on the MS risk could be expected. However, the results described here clearly show a significant effect of Hap4 on the frequency of RTEs.…”