Compromised CD4⁺ CD25^high regulatory T‐cell function in patients with relapsing‐remitting multiple sclerosis is correlated with a reduced frequency of FOXP3‐positive cells and reduced FOXP3 expression at the single‐cell level

Abstract

Summary CD4+ CD25high regulatory T cells (Tregs) of patients with relapsing‐remitting (RR) multiple sclerosis (MS), in contrast to those of patients with secondary progressive (SP) MS, show a reduced suppressive function. In this study, we analysed forkhead box P3 (FOXP3) at the single‐cell level in MS patients and controls (healthy individuals and patients with other neurological diseases) by means of intracellular flow cytometry. Our data revealed a reduced number of peripheral blood CD4+ CD25high FOXP3+ T cells and lower FOXP3 protein expression per cell in RR‐MS patients than in SP‐MS patients and control individuals, which was correlated with the suppressive capacity of Tregs in these patients. Interestingly, interferon (IFN)‐β‐treated RR‐MS patients showed restored numbers of FOXP3+ Tregs. Furthermore, a higher percentage of CD4+ CD25high FOXP3+ Tregs in RR‐MS patients, as compared with controls and SP‐MS patients, expressed CD103 and CD49d, adhesion molecules involved in T‐cell recruitment towards inflamed tissues. This was consistent with a significantly increased number of CD27+ CD25high CD4+ T cells in the cerebrospinal fluid (CSF), as compared with peripheral blood, in RR‐MS patients. Taken together, these data show aberrant FOXP3 expression at the single‐cell level correlated with Treg dysfunction in RR‐MS patients. Our results also suggest that Tregs accumulate in the CSF of RR‐MS patients, in an attempt to down‐regulate local inflammation in the central nervous system.

MicroRNAs targeting TGFβ signalling underlie the regulatory T cell defect in multiple sclerosis

“…Previous studies have shown that patients with multiple sclerosis have Tregs with reduced suppressive function and a retracted TCR repertoire (Viglietta et al, 2004;Haas et al, 2005Haas et al, , 2007Huan et al, 2005;Kumar et al, 2006;Venken et al, 2008). Interestingly, similar observations of reduced Treg function and TCR diversity has been reported in mice deficient in TGFb signalling (Gorelik and Flavell, 2000;Marie et al, 2005Marie et al, , 2006Liu et al, 2008;Ouyang et al, 2010).…”

“…Although there has been some controversy as to whether patients with multiple sclerosis have a reduced number of Tregs, the majority of studies suggest that the defect is not in number but in function (Viglietta et al, 2004;Haas et al, 2005Haas et al, , 2007Huan et al, 2005;Kumar et al, 2006;Venken et al, 2008). In mice with deficiencies in TGFb signalling, the number of Tregs in adult mice is normal; however, the number of Tregs postnatally is significantly reduced (Marie et al, 2005;Liu et al, 2008;Ouyang et al, 2010).…”

“…TGFb is a cytokine known to be particularly important in the development and function of regulatory T cells (Tregs) (Yamagiwa et al, 2001;Zheng et al, 2002;Chen et al, 2003), protectors against autoimmune responses (Suri-Payer et al, 1998;Itoh et al, 1999;Sakaguchi, 2004). Tregs in patients with multiple sclerosis, while normal in number, demonstrate diminished suppressive effect on myelin-specific autoreactive T cells, low FOXP3 expression, and a less diverse T cell receptor (TCR) repertoire (Viglietta et al, 2004;Haas et al, 2005Haas et al, , 2007Huan et al, 2005;Kumar et al, 2006;Venken et al, 2008).…”

Immunomonitoring Lymphocyte Subpopulations in Multiple Sclerosis Patients

“…Moreover, Th17Th1 cells, a subpopulation which secretes both IL-17 and IFN-γ, have also been related to MS pathogenesis (29). Regarding Treg subpopulations, most of the reports found a similar percentage of Tregs in MS patients compared with healthy donors, although a functional impairment has been found in in vitro assays (30)(31)(32). In this context, an increase of the Th17/Treg balance has been associated with higher disease activity and severity (20,33).…”

Western lifestyle and immunopathology of multiple sclerosis

“…16 and 17). Furthermore, decreased forkhead box P3 (FOXP3) and cytotoxic T lymphocyte–associated antigen 4 (CTLA‐4) expression is noted in many MS patients 18, 19…”