Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis
Anne L. Astier, … , Samuel Freeman, David A. Hafler
Anne L. Astier, … , Samuel Freeman, David A. Hafler
Published December 1, 2006
Citation Information: J Clin Invest. 2006;116(12):3252-3257. https://doi.org/10.1172/JCI29251.
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Research Article Autoimmunity

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+CD25high 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.

Authors

Anne L. Astier, Gregory Meiffren, Samuel Freeman, David A. Hafler

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Figure 3

Defect in IL-10 production is independent of the strength of T cell stimulation.

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Defect in IL-10 production is independent of the strength of T cell stim...
(A) A group of patients with MS was either stimulated with 2 μg/ml or 10 μg/ml of anti-CD3 and anti-CD46 antibodies, and cytokine production was determined by ELISA. Although increasing CD46 cross-linking augmented IL-10 production by T cells from both healthy controls and patients with MS, there was still a significant difference between these 2 groups, with lower IL-10 secretion in patients with MS. Average IL-10 production (pg/ml): controls = 1,539, MS = 508 at 1 μg/ml; controls = 2,684, MS = 818 at 10 μg/ml. Average IFN-γ secretion: controls = 5,021, MS = 2,656 at 1 μg/ml; controls = 6,781, MS = 2,466 at 10 μg/ml. (B) T cells were stimulated at either 2 μg/ml or 10 μg/ml of anti-CD3 and anti-CD46 antibodies in the presence of increasing concentrations of IL-2, and proliferation as well as IL-10 secretion were measured. The levels of cytokine secreted were normalized to the proliferation by calculating the ratio of proliferation to IL-10 production.