CD46 processing: a means of expression

Abstract

CD46 is a ubiquitously expressed type I transmembrane protein, first identified as a regulator of complement activation, and later as an entry receptor for a variety of pathogens. The last decade has also revealed the role of CD46 in regulating the adaptive immune response, acting as an additional costimulatory molecule for human T cells and inducing their differentiation into Tr1 cells, a subset of regulatory T cells. Interestingly, CD46 regulatory pathways are defective in T cells from patients with multiple sclerosis, asthma and rheumatoid arthritis, illustrating its importance in regulating T cell homeostasis. Indeed, CD46 expression at the cell surface is tightly regulated in many different cell types, highlighting its importance in several biological processes. Notably, CD46 is the target of enzymatic processing, being cleaved by metalloproteinases and by the presenilin/gamma secretase complex. This processing is required for its functions, at least in T cells. This review will summarize the latest updates on the regulation of CD46 expression and on its effects on T cell activation.

Figure 1. Representation of the four main isoforms of CD46

These isoforms arise from the alternative splicing of exon B, giving rise to a BC or C isoform. The exon coding for Cyt1 can also be spliced to produce either Cyt1 or Cyt2 tail. As Cyt1 contains a stop codon, Cyt1 and Cyt2 sequences are different. Hence, the four main isoforms are BC1, C1, BC2 and C2.

Figure 2. Proposed model of the role of CD46 processing on T cell activation

Upon CD46 co-activation, CD46 is cleaved by a metalloproteinase (MMP), resulting in the release of soluble CD46 in the milieu. sCD46 is likely to retain its binding function, suggesting a potential ability to further regulate T cell activation or neighboring cells. CD46 Cyt1 cytoplasmic tail is then cleaved by the presenilin/γ-secretase concomitantly with an increased in Cyt2 expression. This provides an “on” signal for T cells, resulting in proliferation, IL-10 secretion, and increased CD25 expression. Cleavage of Cyt2 by the P/γS terminates T cell activation by inhibiting T cell proliferation, decreasing IFNγ production and CD25 expression.