Methyl-vitamin B12 blocks the CD28 co-stimulatory pathway in human T cells and its possible therapeutic application for T cell-mediated diseases, including rheumatoid arthritis

Abstract

The effects of metyl-vitamin B12 have been examined on human T cell activation induced by stimulation of T cell receptor (TCR)-CD3 and an accessory molecule, CD28. When T cells in the presence of 10% mitomycin-treated non-T cells were stimulated with anti-CD3 mAb at the optimal concentration, methyl-B12 did not inhibit T cell proliferation. However, when T cells were stimulated with the suboptimal concentration of anti-CD3 and anti-CD28 mAbs, methyl-B12 exhibited potent inhibition of T cell proliferation. Methyl-B12 did not affect cell surface expression of the CD3 and CD28 molecules of T cells. Methyl-B12 inhibited a 29 kDa protein tyrosine phosphorylation that was specifically induced by anti-CD3 and anti-CD28 mAbs. Similarly, T cell proliferation of patients with rheumatoid arthritis (RA), which is representative of T cell-mediated disease was inhibited by methyl-B12, when T cells were stimulated by anti-CD3 and anti-CD28 mAbs. These results suggest that methyl-B12 modulates lymphocyte function through blockade of the CD28 signaling pathway and that methyl-B12 may have T cell inhibitory activity that is applicable for treating patients with RA.