Unfolded Protein Response and Autophagy in T Helper Cell Effector Function

University Of New Mexico Health Scis Ctr, Albuquerque NM

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Abstract

Project Summary The function of T helper (TH) cells, the central organizers of adaptive immunity, is specified by the effector cytokines they produce. Regulation of TH cell cytokine secretion is not well understood and represents an important gap in our knowledge. Our recent data indicate that membrane- associated nucleic acid binding protein (Mnab, encoded by Rc3h2) is required for TH cell effector cytokine secretion. Mnab shares with its paralog Roquin (encoded by Rc3h1) a highly conserved N-terminus but possesses a unique hydrophobic C-terminus. Roquin is important for control of follicular helper T (Tfh) cell development through repression of Icos mRNA. 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. Our preliminary studies demonstrated that a Mnab deficiency led to profound defects in effector cytokine production in TH1, TH2 and TH17 cells, which differs from its known function, suggesting an important role of the distinct C-terminus of Mnab. Based on our preliminary data, we formulate a novel hypothesis: Mnab targets mRNAs encoding proteins in the stress response-autophagy pathway, a common pathway that is critical in TH cell effector cytokine production. The overall specific aims of this project are: Aim 1. Determine the role of Mnab and UPR-autophagy in TH cell function. Aim 2. Delineate the molecular mechanism whereby Mnab controls mRNA stability. Aim 3. Determine the role of Mnab in TH cell function in vivo using disease models. By addressing our hypothesis, these studies will reveal a novel post-transcription control mechanism of TH cell effector function. Manipulation of the corresponding pathways may be of therapeutic benefit in human disease, such as autoimmune and inflammatory disorders.