Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis

Abstract

Loss of Treg function appears to be a critical factor in the pathogenesis of human autoimmune diseases. Attention has focused on defects of CD4 + CD25 high Tregs, and techniques have been developed to determine their function. In contrast, the role of Tr1 regulatory T cells, which secrete the antiinflammatory cytokine IL-10, in autoimmune disease has not been well assessed. CD46 is a newly defined costimulatory molecule for T cell activation, and CD46-costimulated human T cells induce a Tr1 Treg phenotype with considerable amounts of IL-10 secretion. Here, we examined the role of Tr1 cells in patients with multiple sclerosis (MS) by stimulating CD4 + T cells with anti-CD3 and -CD46 mAbs and measuring IL-10 secretion. There were striking defects in the induction of Tr1 cells with CD46 costimulation as measured by IL-10 but not IFN-γ secretion in patients with MS compared with healthy subjects. This loss of Tr1 cell-associated IL-10 secretion was specific to CD46 and not CD28 costimulation and was associated with an altered regulation of the CD46-Cy2 isoform that differentially regulates T cell function in a CD46-transgenic murine model. These data demonstrate a second major Treg defect in human autoimmune disease associated with the CD46 pathway.

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 .…”

Pharmacodynamic effects of daclizumab in the intrathecal compartment

“…Furthermore, daclizumab actually inhibits FoxP3 + Treg activation, proliferation, and numbers 14. Therefore, the daclizumab‐induced increase in CSF IL‐2 levels indicate that at least part of the residual intrathecal T‐cell population includes effector T cells, or regulatory T cells other than FoxP3 + Treg, such as Tr1 cells 22. Remaining CNS T cells may hypothetically retain some advantage over treatments that abrogate CNS immunosurveillance from the standpoint of patient safety and by permitting “beneficial autoimmunity,” necessary for the maintenance of adult neurogenesis23 and for neural repair and remyelination 24.…”

Increased IL-23 secretion and altered chemokine production by dendritic cells upon CD46 activation in patients with multiple sclerosis

“…More recently, it was identified as a co-stimulatory molecule for T cell activation (Astier et al, 2000;Marie et al, 2002;Zaffran et al, 2001) and it induces a Tr1 regulatory phenotype with considerable secretion of IL-10 and granzyme B (Grossman et al, 2004;Kemper et al, 2003). This Tr1 differentiation is altered in patients with MS, characterized by a lack of IL-10 production upon CD46 activation (Astier and Hafler, 2007;Astier et al, 2006). Herein, we further investigated the role of CD46 in MS by analyzing its role on mDCs and comparing healthy donors and patients with MS.…”

“…Forty-eight hours later, cells were collected for gene expression assays. For IL-17 expression, CD4 + T cells were isolated as described before (Astier et al, 2006) and cultured at 2×10 6 cells/ml in 48-well plates coated with anti-CD3 mAb (OKT3, 2.5 µg/ml) for 48h with and without mDCs supernatants matured with LPS or LPS plus anti-CD46. …”