Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis

Abstract

Immunoregulatory T cells of CD4 + CD25 + phenotype suppress T cell function and protect rodents from organ-specific autoimmune disease. The human counterpart of this subset of T cells expresses high levels of CD25 and its role in human autoimmune disorders is currently under intense investigation. In multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), the activation of circulating self-reactive T cells with specificity for myelin components is considered to be an important disease initiating event. Here, we investigated whether MS is associated with an altered ability of CD4 + CD25 high regulatory T cells (T reg ) to confer suppression of myelin-specific immune responses. Whereas T reg frequencies were equally distributed in blood and cerebrospinal fluid of MS patients and did not differ compared to healthy controls, the suppressive potency of patient-derived CD4 + CD25 high T lymphocytes was impaired. Their inhibitory effect on antigen-specific T cell proliferation induced by human recombinant myelin oligodendrocyte protein as well as on immune responses elicited by polyclonal and allogeneic stimuli was significantly reduced compared to healthy individuals. The effect was persistent and not due to responder cell resistance or altered survival of T reg , suggesting that a defective immunoregulation of peripheral T cells mediated by CD4 + CD25 high T lymphocytes promotes CNS autoimmunity in MS.

Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus

“…Accordingly, the frequency of CD95ϩ Treg in whole PBMC fractions in patients with CLE was not lower than that in normal healthy donors. We also did not observe increased CD95L-mediated cell death or enhanced CD95 expression in a cohort of patients with newly diagnosed multiple sclerosis (30). Therefore, the question remains open whether enhanced sensitivity to apoptosis of Treg can contribute to autoimmune diseases.…”

“…CD4ϩ,CD25 high Treg and CD4ϩ,CD25 low /CD4ϩ,CD25 Ϫ Treg were isolated from the pure, untouched CD4ϩ T cells using CD25 magnetic beads (Miltenyi Biotech). Titration of magnetic beads and optimization of further conditions (temperature, column flow rate, incubation time) allowed for a more rapid Treg isolation (Ͻ2 hours) than that achieved with FACS, at a similar purity of at least 82% (30). Further characterization of magnetically isolated Treg showed a suppressive capacity similar to that of Treg sorted by FACS and similar levels of Foxp3 expression, as determined by quantitative reverse transcription-polymerase chain reaction (data not shown).…”

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

“…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).…”

CD4+ T cells from multiple sclerosis patients respond to a commensal‐derived antigen

“…This result is of potentially important clinical value since T reg function is known to be impaired in patients with MS 1, 2, 3. Since suppressive function often corresponds to the production of IL‐10, we next determined if stimulation with PSA resulted in an increase in IL‐10 production.…”

“…It is believed that the fluctuation between relapse and remission is greatly influenced by the balance of self‐reactive effector T cells and regulatory T cells (T regs ). Importantly, studies have shown that while MS patients harbor normal frequencies of T regs , their production of IL‐10 and overall suppressive capacity is significantly reduced allowing for increased inflammation driven by effector cells 1, 2, 3. For many years, the immunopathogenesis of this condition was attributed to an imbalance of Th1/Th2 polarization in which the enhanced Th1 response was associated with the production of IFN γ and TNF α .…”