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.
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. In our preliminary studies, we found that in vitro, deficiency of membrane-associated nucleic acid binding protein (Mnab) led to profound defects in TH cell effector cytokine production. How Mnab regulates TH cell effector function is entirely unclear. We hypothesize that Mnab modulates stability of mRNAs encoding proteins in a common pathway that is critical in TH cell cytokine production. Our current data support a novel hypothesis that Mnab stabilizes mRNAs in the stress response-autophagy pathway that is required for secretory cells. In the proposed study, we will further understand how Mnab controls TH cell cytokine secretion and whether Mnab regulates TH cell function in disease models. Our studies will reveal a novel post-transcriptional 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.
| Tasnim, Humayra; Fricke, G Matthew; Byrum, Janie R et al. (2018) Quantitative Measurement of Naïve T Cell Association With Dendritic Cells, FRCs, and Blood Vessels in Lymph Nodes. Front Immunol 9:1571 |
| Castillo, Eliseo F; Zheng, Handong; Yang, Xuexian O (2018) Orchestration of epithelial-derived cytokines and innate immune cells in allergic airway inflammation. Cytokine Growth Factor Rev 39:19-25 |
| Zheng, Handong; Wu, Dandan; Wu, Xiang et al. (2018) Leptin Promotes Allergic Airway Inflammation through Targeting the Unfolded Protein Response Pathway. Sci Rep 8:8905 |
| Deretic, Vojo; Klionsky, Daniel J (2018) Autophagy and inflammation: A special review issue. Autophagy 14:179-180 |
| Zhang, Xing; Luo, Yan; Wang, Chunqing et al. (2018) Adipose mTORC1 Suppresses Prostaglandin Signaling and Beige Adipogenesis via the CRTC2-COX-2 Pathway. Cell Rep 24:3180-3193 |
| Kumar, Suresh; Jain, Ashish; Farzam, Farzin et al. (2018) Mechanism of Stx17 recruitment to autophagosomes via IRGM and mammalian Atg8 proteins. J Cell Biol 217:997-1013 |
| Claude-Taupin, Aurore; Bissa, Bhawana; Jia, Jingyue et al. (2018) Role of autophagy in IL-1? export and release from cells. Semin Cell Dev Biol 83:36-41 |
| Deretic, Vojo; Levine, Beth (2018) Autophagy balances inflammation in innate immunity. Autophagy 14:243-251 |
| Jia, Jingyue; Abudu, Yakubu Princely; Claude-Taupin, Aurore et al. (2018) Galectins Control mTOR in Response to Endomembrane Damage. Mol Cell 70:120-135.e8 |
| Choi, Seong Won; Gu, Yuexi; Peters, Ryan Scott et al. (2018) Ambroxol Induces Autophagy and Potentiates Rifampin Antimycobacterial Activity. Antimicrob Agents Chemother 62: |
Showing the most recent 10 out of 11 publications
