Processing and glycosylation of CD46 regulate : its expression and T cell responses

CD46 is a ubiquitously expressed transmembrane molecule and has an important role in the innate and adaptive immune system. CD46 was originally identified as a complement receptor that protects cells from autologous attack. However, CD46’s immunological profile is ever expanding and more recently it was identified as a T cell costimulatory molecule. Notably, in the presence of IL-2, CD46 can induce a Tr1-like phenotype that is characterized by the secretion of large amounts of the potent anti-inflammatory cytokine, IL-10. Defects in CD46- induced IL-10 secretion have been identified in multiple sclerosis, asthma and rheumatoid arthritis. Despite CD46’s promiscuous nature in immune responses there is little known about its underlying processing and signalling pathways. Herein, I report that CD46 expression and processing are important for regulating T cell anti-inflammatory responses and activation. Cyt1 but not Cyt2 promotes an increased ratio IL-10+ cells compared to cells that secrete both Il-10 and IFNγ. Upon CD46 costimulation, proteolytic cleavage of CD46 occurs at the surface and intracellularly with the subsequent release of a functional intracellular domain (ICD). As a result of alternative splicing, there are two main cytoplasmic isoforms of CD46, both of which release ICDs, Cyt1 and Cyt2. It is shown that the smaller Cyt1 ICD fragment facilitates T cell activation, whereas, Cyt2 promotes T cell activation when expressed in an uncleaved form. As the expression and cleavage of CD46 is important for regulating T cell function, I went on to identify factors that can regulate CD46 cleavage. Herein, it is demonstrated that T cell activation by the T cell receptor (TCR) acts as a major regulator of CD46 cleavage and expression, emphasizing the inherent role of CD46 in T cell activation. TCR stimulation also modulates CD46 glycosylation, which may effect CD46 expression and T cell phenotype. Importantly, I have identified a dysregulated expression of CD46 in a preliminary cohort of RRMS patients. It will be interesting to examine if aberrant CD46 glycosylation or cleavage accounts for its altered expression levels and impaired IL-10 secretion in RRMS patients.