CD4+CD25+ T regulatory cells in multiple sclerosis

Multiple sclerosis (MS) is a chronic, inflammatory, and demyelinating disease of the central nervous system (CNS), which is likely to be mediated by autoaggressive immunity. Treatments of MS that may beneficially influence the disease course consist of Avonex (interferon-beta; IFN-beta), and Copaxone (glatiramer acetate; GA). Studies in experimental autoimmune encephalomyelitis (EAE), a commonly used experimental model of human MS, have demonstrated a crucial role of CD4+CD25+ T regulatory (Tr) cells in suppressing autoreactive T cells and promoting peripheral tolerance. Recent studies have shown that Tr cells inhibiting the proliferation and cytokine secretion by CD4+ T cells, are enriched in the CD25high cells among CD4+ T cells. It is not yet known if circulating CD4+CD25 high Tr cells are involved in MS.

The aims of this study were to:

1. identify and quantify CD4+CD25+ and CD4+CD25high Tr cells among blood CD4+ T cells, and proportions of CD4+CD25high Tr cells expressing cell surface and intracellular molecules in patients with untreated MS vs MS treated with either IFN-beta-1a or GA or the combination of IFN-beta-1a+GA vs healthy controls (HC);

2. to correlate the properties of circulating CD4+CD25+ Tr cells with lesion load (LL) and gadolinium (Gd) enhancement detected by magnetic resonance imaging (MRI) of the brain in untreated MS patients.

3. analyse the in-vitro influence of GA upon CD4+CD25 high Tr cells from MS patients vs from HC.

4. examine whether a functional deficit inherent to CD4+CD25+ Tr cells occurred in untreated MS patients vs HQ in terms of the ability of Tr cells to suppress the production of pro-inflammatory cytokines by blood mononuclear cells (MNC) upon auto- or foreign-antigenic stimulation.

These studies demonstrated that i) there are no alterations of frequency of circulating CD4+CD25+ and CD4+CD25high Tr cells nor of the proportions of CD4+CD25 high Tr cells expressing CD45RO, HLADR, CD95, CTLA-4 or IL-10 in MS patients compared to HQ ii) the frequency of CD4+CD25+ Tr cells, and the proportions of IL-10 expressing CD4+CD25+ Tr cells are elevated in MS patients with Gdenhancing lesions; iii) the proportion of CXCR3+ CD4+ T cells is lower in the group of patients with Gdenhancing lesions on T1weighted images, as compared to the group with no Gd-enhancing lesions; iv) GA, in vitro elevates the levels of IL-10 producing blood CD4+CD25 high Tr cells in both MS patients and HC, and; v) CD4+CD25+ Tr cells augments the secretion of Th1 cytokines IFN-gamma and IL-2, but not of Th.2 cytokine IL-13 in response to MBP, equally in MS patients and HC, suggesting that the functional activity of CD4+CD25+ Tr cells in terms of controlling Th1 and Th2 cytokine secretions in response to MBP, is not significantly altered in MS.

List of scientific papers

I. Putheti P, Pettersson A, Soderstrom M, Link H, Huang YM (2004). Circulating CD4(+)CD25(+) T Regulatory Cells Are Not Altered in Multiple Sclerosis and Unaffected by Disease-Modulating Drugs. J Clin Immunol. 24(2): 155-61.
https://pubmed.ncbi.nlm.nih.gov/15024182

II. Putheti P, Morris M, Stawiarz L, Teleshova N, Kivisakk P, Pashenkov M, Kouwenhoven M, Wiberg MK, Bronge L, Huang YM, Soderstrom M, Hillert J, Link H (2003). Multiple sclerosis: a study of chemokine receptors and regulatory T cells in relation to MRI variables. Eur J Neurol. 10(5): 529-35.
https://pubmed.ncbi.nlm.nih.gov/12940835

III. Putheti P, Soderstrom M, Link H, Huang YM (2003). Effect of glatiramer acetate (Copaxone) on CD4+CD25high T regulatory cells and their IL-10 production in multiple sclerosis. J Neuroimmunol. 144(1-2): 125-31.
https://pubmed.ncbi.nlm.nih.gov/14597106

IV. Ptheti P, Pashenkov M, Huang YM, Soderstrom M, Link H (2004). Multiple sclerosis: No evidence of functional deficit of CD4+CD25+T regulatory cells. [Manuscript]