We are constantly protected by our adaptive immune system. Its functioning requires precise control of gene expression in lymphocytes, since deregulation can cause autoimmune diseases (affecting ~5% of our population) as well as allergic reactions (~9-16%, with increasing incidence). Post-transcriptional control of gene expression is crucial in many immune decisions, however the determinants of specificity in this type of regulation are less well defined. The recently described Rc3h1 or Roquin protein prevents the development of autoimmune disease in mice. Rc3h1 destabilizes the mRNA of the inducible costimulator (ICOS), a co-receptor on T cells. ICOS is critical in the germinal center reaction in which T cell help selects B cells making high affinity antibodies. However, the molecular interactions of this posttranscriptional regulation and the pathways that specify such repressor/target relations are unsolved, and they are the focus of my work in this proposal.Rc3h1 is an essential factor of peripheral T cell tolerance, whereas the role of its paralog Rc3h2 has not been addressed. We have recently shown that Rc3h1 is an RNA binding-protein that recognizes the 3’UTR of ICOS mRNA. Our preliminary data suggest that Rc3h2 is co-expressed in T cells and binds ICOS mRNA indistinguishably in vitro, however it does not repress ICOS. Major challenges are therefore to define how the Rc3h1/2 proteins recognize cis-elements in the RNA, which cofactors they require for repression and how these proteins exert diverse functions. My project proposes to pursue three aims: (1) to describe Rc3h1/2 target recognition in the T cell transcriptome, (2) to globally identify the essential genes in this pathway of post-transcriptional repression and (3) to analyze redundant and unique roles of Rc3h1 and Rc3h2 proteins in the mouse embryo, the hematopoietic system and in models of immunity and spontaneous development of autoimmune disease.