Regulation of T helper cell effector function

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DESCRIPTION (provided by applicant): T helper (TH) cells are the central organizers of adaptive immunity. TH cell function is specified by the effector cytokines they produce. Regulation of TH cell cytokine secretion is not well understood. Our recent data indicate that membrane-associated nucleic acid binding protein ([Mnab], also termed Roquin2, encoded by Rc3h2) is involved in control of TH cell effector function. Mnab shares with its paralog Roquin (encoded by Rc3h1) a highly conserved amino (N)- terminus that bears RING, ROQ and CCCH domains, whereas Mnab possesses a unique hydrophobic C-terminus. Roquin, an RNA-binding protein, interacts with Icos messenger RNA (mRNA) through its ROQ and CCCH-zinc finger domains, thereby regulating its stability and turnover. Sanroque mice, bearing a single point mutation (M199R) in the ROQ domain of Roquin, develop an autoimmune syndrome resembling systemic lupus erythematosus (SLE) in humans due to increased expression of ICOS on T cells and overrepresented follicular helper T (Tfh) cell compartment in the CD4+ T cells. Recently, Mnab was shown to play a redundant role with Roquin in Tfh cell development via repression of Icos and Ox40 mRNAs. Whether Mnab also targets other mRNAs and regulates function of other TH lineages is unclear. In our preliminary studies, we found that in vitro, Mnab deficiency in both RING and ROQ domains led to profound defects of effector cytokine production in TH1, TH2 and TH17 cells, suggesting an important role of its distinct hydrophobic C-terminus. The overall objective of this project is to determine the role of Mnab in TH cell effector function and the molecular basis. Our central hypothesis is that Mnab targets mRNAs encoding proteins in a common pathway that is critical in TH cell effector cytokine production. Our current data support that instead, Mnab stabilizes mRNAs in the stress pathway that is required for the secretory cells. In this proposal, we will first, determine the role of Mnab in TH cell differentiation and function in vitro and in vivo; second, determine the mRNA targets of Mnab in TH cells; third, determine the mechanism by which Mnab modulates mRNA stability. This study will reveal mechanistic information of TH cell effector function. Manipulation of the corresponding pathways may be of therapeutic benefit in human disease, such as autoimmune disorders.