T-cell regulation by CD46 and its relevance in multiple sclerosis

Abstract

CD46 is a complement regulatory molecule expressed on every cell type, except for erythrocytes. While initially described as a regulator of complement activity, it later became a 'magnet for pathogens', binding to several viruses and bacteria. More recently, an alternative role for such complement molecules has emerged: they do regulate T-cell immunity, affecting T-cell proliferation and differentiation. In particular, CD46 stimulation induces Tr1 cells, regulatory T cells characterized by massive production of interleukin-10 (IL-10), a potent anti-inflammatory cytokine. Hence, CD46 is likely to control inflammation. Indeed, data from CD46 transgenic mice highlight a role for CD46 in inflammation, with antagonist roles depending on the cytoplasmic tail being expressed. Furthermore, recent data have shown that CD46 is defective in multiple sclerosis, IL-10 production being severely impaired in these patients. This lack of IL-10 production probably participates in the inflammation observed in patients with multiple sclerosis. This review will summarize the data on CD46 and T cells, and how CD46 is likely involved in multiple sclerosis.

Figure 1

Schematic structure of CD46 cytoplasmic isoforms. The two cytoplasmic isoforms, C1 and C2, derived from the alternative splicing of the Cyt1 exon. They exhibit different sequences, because of the stop codon present in the Cyt1 sequence. CCP, complement control protein modules.

Figure 2

Opposite role of CD46 cytoplasmic isoforms in inflammation. C1 and C2 isoforms were expressed in transgenic mice, and the hypersensitivity contact reaction to dinitrofluorobenzene was assessed in each strain, after stimulation by heat-inactivated measles virus (which binds to CD46). Purified T cells were then costimulated in vitro by CD3/CD46, and proliferation, cytokine production and cytotoxicity were determined.