title: The dynamic processing of CD46 intracellular domains provides a molecular rheostat for T cell activation.
abstract: BACKGROUND
  Adequate termination of an immune response is as important as the induction of an appropriate response. CD46, a regulator of complement activity, promotes T cell activation and differentiation towards a regulatory Tr1 phenotype. This Tr1 differentiation pathway is defective in patients with MS, asthma and rheumatoid arthritis, underlying its importance in controlling T cell function and the need to understand its regulatory mechanisms. CD46 has two cytoplasmic tails, Cyt1 and Cyt2, derived from alternative splicing, which are co-expressed in all nucleated human cells. The regulation of their expression and precise functions in regulating human T cell activation has not been fully elucidated.
  
  
  RESULTS
  Here, we first report the novel role of CD46 in terminating T cell activation. Second, we demonstrate that its functions as an activator and inhibitor of T cell responses are mediated through the temporal processing of its cytoplasmic tails. Cyt1 processing is required to turn T cell activation on, while processing of Cyt2 switches T cell activation off, as demonstrated by proliferation, CD25 expression and cytokine secretion. Both tails require processing by Presenilin/γSecretase (P/γS) to exert these functions. This was confirmed by expressing wild-type Cyt1 and Cyt2 tails and uncleavable mutant tails in primary T cells. The role of CD46 tails was also demonstrated with T cells expressing CD19 ectodomain-CD46 C-Terminal Fragment (CTF) fusions, which allowed specific triggering of each tail individually.
  
  
  CONCLUSIONS
  We conclude that CD46 acts as a molecular rheostat to control human T cell activation through the regulation of processing of its cytoplasmic tails.
authors.affiliation: Institute of Immunology and Infection Research, Edinburgh, United Kingdom.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Ni Choileain
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Weyand
authors.forename: Christian
authors.initials: C
authors.lastname: Neumann
authors.forename: Joelle
authors.initials: J
authors.lastname: Thomas
authors.forename: Magdalene
authors.initials: M
authors.lastname: So
authors.forename: Anne L
authors.initials: AL
authors.lastname: Astier
mesh_terms: D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008213:Lymphocyte Activation; D051916:Membrane Cofactor Protein / Q000378:metabolism*; D053763:Presenilins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology
chemical_list: C497857:CD46 protein, human; D051916:Membrane Cofactor Protein; D053763:Presenilins