PhD – University of Rochester, Rochester, NY
Immune Signaling and Metabolism
The underlying theme of our research is to understand the mechanisms of immune signaling and cell metabolism that control the differentiation and function of T cells, a central cell type in adaptive immunity. We use a combination of experimental systems including mouse genetics, cellular immunology and biochemistry, as well as models of autoimmune and infectious diseases and cancer. More recently, we apply systems biology approaches, such as proteomics, metabolomics, single cell RNA-sequencing (scRNA-Seq), CRISPR screening and integrative network analysis, to reconstruct metabolic signaling circuits and identify new therapeutic targets. Within the underlying theme of our research, we explore T cell responses from two complementary angles: the molecular pathways intrinsic to T cells, and the pathways that act in dendritic cells to cross-regulate T cell responses. For T cell-intrinsic mechanisms, we have been particularly interested in mTOR, Hippo and metabolic pathways that control the differentiation and function of regulatory and effector T cells (See Wei Nature 2019; Karmaus Nature 2019; Shi Immunity 2019; Shi Immunity 2018; Yang Science Immunology 2018; Yang Nature 2017; Tan Immunity 2017; Wei Nature Immunology 2016; Zeng Immunity 2016; Shrestha Nature Immunology 2015; Zeng Nature 2013; Yang Immunity 2013). For dendritic cell-mediated extrinsic control of T cell differentiation, we have focused on metabolic and inflammatory pathways (see Du Nature 2018; Huang Nature Immunology 2012; Huang Immunity 2011). Significant insight into the physiological roles of signaling and metabolic pathways could impact our understanding of fundamental mechanisms of immune regulation and manifest legitimate therapeutic opportunities.
Wei J, Long L, Zheng W, Dhungana Y, Lim SA, Guy C, Wang Y, Wang YD, Qian C, Xu B, Kc A, Saravia J, Huang H, Yu J, Doench JG, Geiger TL, Chi H. Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy. Nature 576:471–476; Dec 11, 2019. doi: 10.1038/s41586-019-1821-z. (see News and Views in the same issue, doi: 10.1038/d41586-019-03731-w)
Du X, Zeng H, Liu S, Guy C, Dhungana Y, Neale G, Bergo MO, Chi H. Mevalonate metabolism-dependent protein geranylgeranylation regulates thymocyte egress. J Exp Med. 217(2):e20190969; Feb 3, 2020. doi: 10.1084/jem.20190969.
Shi H, Chapman NM, Wen J, Guy C, Long L, Dhungana Y, Rankin S, Pelletier S, Vogel P, Wang H, Peng J, Guan KL, Chi H. Amino Acids License Kinase mTORC1 Activity and Treg Cell Function via Small G Proteins Rag and Rheb. Immunity 51:1012-1027, 2019.
Chapman NM, Boothby MR, Chi H. Metabolic coordination of T cell quiescence and activation. Nat Rev Immunol Aug 12, 2019. (review)
Wang Y, Du X, Wei J, Long L, Tan H, Guy C, Dhungana Y, Qian C, Neale G, Fu YX, Yu J, Peng J, Chi H. LKB1 orchestrates dendritic cell metabolic quiescence and anti-tumor immunity. Cell Res 29:391-405, 2019.
Saravia J, Chapman NM, Chi H. Helper T cell differentiation. Cell Mol Immunol 16:634-643, 2019. (review)
Karmaus PWF, Chen X, Lim SA, Herrada AA, Nguyen TM, Xu B, Dhungana Y, Rankin S, Chen W, Rosencrance C, Yang K, Fan Y, Cheng Y, Easton J, Neale G, Vogel P, Chi H. Metabolic heterogeneity underlies reciprocal fates of TH17 cell stemness and plasticity. Nature 565:101-105, 2019.
Shi H, Liu C, Tan H, Li Y, Nguyen TL, Dhungana Y, Guy C, Vogel P, Neale G, Rankin S, Feng Y, Peng J, Tao W*, Chi H*. Hippo kinases Mst1/Mst2 sense and amplify IL-2R−STAT5 signaling in regulatory T cells to establish stable regulatory activity. Immunity 49:899-914, 2018. * Shared senior authorship.
Yang K, Blanco DB, Chen X, Dash P, Neale G, Rosencrance C, Easton J, Chen W, Dhungana Y, KC A, Awad W, Guo XZ, Thomas P, Chi H. Metabolic signaling directs the reciprocal lineage decisions of ab and gd T cells. Sci Immunol 3(25). pii: eaas9818, 2018. (cover story)
Du X, Wen J, Wang Y, Karmaus PWF, Khatamian A, Tan H, Li Y, Guy C, Nguyen TM, Dhungana Y, Neale G, Peng J, Yu J*, Chi H*. Hippo/Mst signalling couples metabolic state and immune function of CD8α+ dendritic cells. Nature 558:141-145, 2018. *Shared senior authorship.
Chapman NM, Zeng H, Nguyen TM, Wang Y, Vogel P, Dhungana Y, Liu X, Neale G, Locasale JW, Chi H. mTOR coordinates transcriptional programs and mitochondrial metabolism of activated Treg subsets to protect tissue homeostasis. Nat Commun 9:2095, 2018.
Zeng H, Yu M, Tan H, Li Y, Su W, Shi H, Dhungana Y, Guy C, Neale G, Cloer C, Peng J*, Wang D*, Chi H*. Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7-driven B lymphopoiesis. Sci Adv 4:eaar5701, 2018. *Shared senior authorship.
Yang K, Blanco DB, Neale G, Vogel P, Avila J, Clish CB, Wu C, Shrestha S, Rankin S, Long L, Kc A, Chi H. Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling. Nature 548:602-606, 2017.
Karmaus PWF, Herrada AA, Guy C, Neale G, Dhungana Y, Long L, Vogel P, Avila J, Clish CB, Chi H. Critical roles of mTORC1 signaling and metabolic reprogramming for M-CSF-mediated myelopoiesis. J Exp Med 214:2629-2647, 2017.
Zeng H, Chi H. mTOR signaling in the differentiation and function of regulatory and effector T cells. Curr Opin Immunol 46:103-111, 2017. (review)
Wei J, Raynor J, Nguyen TL, Chi H. Nutrient and Metabolic Sensing in T Cell Responses. Front Immunol 8:247, 2017. (review)
Tan H, Yang K, Li Y, Shaw TI, Wang Y, Blanco DB, Wang X, Cho JH, Wang H, Rankin S, Guy C, Peng J*, Chi H*. Integrative Proteomics and Phosphoproteomics Profiling Reveals Dynamic Signaling Networks and Bioenergetics Pathways Underlying T Cell Activation. Immunity 46: 488-503, 2017. *Shared senior authorship.
Zeng H, Cohen S, Guy C, Shrestha S, Neale G, Brown SA, Cloer C, Kishton RJ, Gao X, Youngblood B, Do M, Li MO, Locasale JW, Rathmell JC*, Chi H*. mTORC1 and mTORC2 Kinase Signaling and Glucose Metabolism Drive Follicular Helper T Cell Differentiation. Immunity 45:540-554, 2016. *Shared senior authorship.
Wei J, Long L, Yang K, Guy C, Shrestha S, Chen Z, Wu C, Vogel P, Neale G, Green DR, Chi H. Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis. Nat Immunol 17:277-285, 2016. (cover story)
Shi LZ, Saravia J, Zeng H, Kalupahana NS, Guy CS, Neale G, Chi H. Gfi1-Foxo1 axis controls the fidelity of effector gene expression and developmental maturation of thymocytes. Proc Natl Acad Sci USA 114:E67-E74, 2016.
Shrestha S, Yang K, Guy C, Vogel P, Neale G, Chi H. Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat Immunol 16:178-187, 2015. (cover story)
Huang G, Wang Y, Vogel P, Chi H. Control of IL-17 receptor signaling and tissue inflammation by the p38a-MKP-1 signaling axis in a mouse model of multiple sclerosis. Sci Signal 8:ra24, 2015. (cover story)
Zeng H, Chi H. Metabolic control of regulatory T cell development and function.Trends Immunol 36:3-12, 2015. (review)
Shrestha S, Yang K, Wei J, Karmaus PW, Neale G, Chi H. Tsc1 promotes the differentiation of memory CD8+ T cells via orchestrating the transcriptional and metabolic programs. Proc Natl Acad Sci USA 111:14858-14863, 2014.
Wei J, Yang K, Chi H. Cutting edge: Discrete functions of mTOR signaling in invariant NKT cell development and NKT17 fate decision. J Immunol 193:4297-4301, 2014.
Wu J, Yang J, Yang K, Wang H, Gorentla B, Shin J, Qiu Y, Que L, Foster WM, Xia Z, Chi H*, Zhong XP*. iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions. J Clin Invest 124:1685-1698, 2014. *Shared senior authorship.
Zeng H, Yang K, Cloer C, Neale G, Vogel P, Chi H. mTORC1 couples immune signals and metabolic programming to establish Treg cell function. Nature 499: 485–490, 2013.
Yang K, Shrestha S, Zeng H, Karmaus PW, Neale G, Vogel P, Guertin DA, Lamb RF, Chi H. T cell exit from quiescence and differentiation into Th2 cells depend on Raptor-mTORC1-mediated metabolic reprogramming. Immunity 39:1043–1056, 2013.
Shi LZ, Kalupahana NS, Turnis ME, Neale G, Hock H, Vignali DA, Chi H. Inhibitory role of the transcription repressor Gfi1 in the generation of thymus-derive regulatory T cells. Proc Natl Acad Sci USA 110:E3198-3205, 2013.
Wang Y, Huang G, Zeng H, Yang K, Lamb RF, Chi H. Tuberous sclerosis 1 (Tsc1)-dependent metabolic checkpoint controls development of dendritic cells. Proc Natl Acad Sci USA 110:E4894-E4903, 2013.
Huang G, Wang Y, Chi H. Control of T cell fates and immune tolerance by p38α signaling in mucosal CD103+ dendritic cells. J Immunol 191:650-659, 2013.
Zeng H, Chi H. mTOR and lymphocyte metabolism. Cur Opin Immunol 25:347-355, 2013 (review).
Yang K, Chi H. mTOR and metabolic pathways in T cell quiescence and functional activation. Semin Immunol 24:421-428, 2013. (review)
Karmaus PW, Chi H. Genetic dissection of dendritic cell homeostasis and function: lessons from cell type-specific gene ablation. Cell Mol Life Sci Dec. 24, 2013. (review)
Huang G, Wang Y, Vogel P, Kanneganti TD, Otsu K, Chi H. Signaling via the kinase p38α programs dendritic cells to drive TH17 differentiation and autoimmune inflammation. Nat Immunol 13:152-161, 2012.
Wang Y, Huang G, Vogel P, Neale G, Reizis B, Chi H. Transforming growth factor beta-activated kinase 1 (TAK1)-dependent checkpoint in the survival of dendritic cells promotes immune homeostasis and function. Proc Natl Acad Sci USA 109: E343-E352, 2012.
Chi H. Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol 12:325-338, 2012. (review)
Yang K, Neale G, Green DR, He W, Chi H. The tumor suppressor Tsc1 enforces quiescence of naïve T cells to promote immune homeostasis and function. Nat Immunol 12:888-897, 2011.
Huang G, Wang Y, Shi LZ, Kanneganti TD, Chi H. Signaling by the phosphatase MKP-1 in dendritic cells imprints distinct effector and regulatory T cell fates. Immunity 35:45-58, 2011.
Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR*, Chi H*. HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208:1367-1376, 2011. *Shared senior authorship.
Chi H. Sphingosine-1-phosphate and immune regulation: trafficking and beyond. Trends Pharmacol Sci 32:16-24, 2011. (review)
Liu G, Yang K, Burns S, Shrestha S, Chi H. The S1P1-mTOR axis directs the reciprocal differentiation of TH1 and Treg cells. Nat Immunol 11:1047-1056, 2010.
Liu G, Burns S, Huang G, Boyd K, Proia, RL, Flavell RA, Chi H. The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt-mTOR. Nat Immunol 10:769-777, 2009.
Menon S*, Chi H*, Zhang H, Deng X, Flavell RA, Wei N. COP9 Signalosome subunit 8 (Csn8) is essential for peripheral T cell homeostasis and antigen receptor-induced cell cycle entry from quiescence. Nat Immunol 8:1236-1245, 2007. *Equal contribution.
Chi H, Barry SP, Roth RJ, Wu JJ, Jones EA, Bennett AM, Flavell RA. Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses. Proc Natl Acad Sci USA 103:2274-2279, 2006.
Wan YY*, Chi H*, Xie M, Schneider MD, Flavell RA. The kinase TAK1 integrates antigen and cytokine receptor signaling for T cell development, survival and function. Nat Immunol 7:851-858, 2006. *Equal contribution.
Chi H, Flavell RA. Cutting edge: regulation of T cell trafficking and primary immune responses by sphingosine 1-phosphate receptor 1. J Immunol 174:2485-2488, 2005.
Chi H*, Sarkisian MR*, Rakic P, Flavell RA. Loss of mitogen-activated protein kinase kinase kinase 4 (MEKK4) results in enhanced apoptosis and defective neural tube development. Proc Natl Acad Sci USA 102:3846-3851, 2005. *Equal contribution.
Chi H, Lu B, Takekawa M, Davis RJ, Flavell RA. GADD45β/GADD45γ and MEKK4 comprise a genetic pathway mediating STAT4-independent IFNγ production in T cells. EMBO J 23:1576-1586, 2004.
Last update: December 2019