Current Investigators

Chyi-Song Hsieh, MD, PhD


The goal of the laboratory is to understand how the body maintains tolerance to self as well as innocuous foreign antigens such as those derived from food and commensal bacteria, with the belief that this knowledge may eventually be utilized therapeutically in human autoimmune and inflammatory disease. In particular, we are interested in the tolerogenic function of antigen specific CD4 T cells directed towards self and commensal/food antigens. To restrict the diversity of the T cell receptor repertoire to a manageable level, we use T cell receptor-beta chain transgenics to limit the variability in the T cell receptor repertoire to only the T cell receptor-alpha chain. This permits analysis of the T cell receptor repertoire by direct sequencing of the variable T cell receptor-alpha chains. We have accumulated a large database of T cell receptor sequences from normal CD4+ T cells, which will be a useful reference point for understanding autoimmune T cell repertoires. T cell receptors of interest can then be analyzed functionally for their antigen specificity and self-reactivity, as well as for their effects on T cell development. This approach has been useful in our studies of host interactions with food and bacteria in the gut (Nature, 2012; J. Immunol. 2016; Cell Reports, 2016; Sci. Immunol, 2017; eLife, 2021; Immunity, 2021). More recently my laboratory, in collaboration with Dr. Newberry's group in the Division of Gastroenterology, have been investigating how the gut microbiome and mucosal immune responses induced by these microbes impact diseases at distant sites including autoimmune diseases.

MIST Research

The gastrointestinal (GI) tract is a large surface lined by a single layer epithelium which is exposed to trillions of microbes and innocuous substances from the diet. The largest collection of immune cells in the body underlies this single layer epithelium and monitors the luminal contents to maintain tolerance to dietary and commensal antigens in the steady-state while retaining the ability to rapidly induce immunity to pathogens during infection. While great progress has been made in elucidating the role(s) of specific immune cell subsets, cytokines, and other factors promoting tolerance or immunity, the processes intrinsic to the gut that enable the immune system to switch from an overwhelmingly tolerogenic tone in the steady-state to inflammatory responses during infection remains a gap in our understanding. Recently, we have uncovered that inhibiting goblet cell associated antigen passages (GAPs) in the small intestine (SI) rapidly shifts the immunologic tone away from tolerance and promotes the rapid induction of inflammatory Th17 responses in the absence of infection or injury. We hypothesize that the inhibition of GAPs is a physiologic response to enteric infection, which in and of itself, promotes the generation of Th17 cells and inflammatory cytokines and shifts the tone of the immune system away from tolerance toward immunity. By studying this process in the absence of enteric infection or injury we can disentangle contributions of the pathogen and injury to the inflammatory response from intrinsic properties of the gut ecosystem promoting the switch from a tolerogenic to pro-inflammatory state. Understanding intrinsic properties of the gut that allows the rapid generation of protective responses could provide new approaches to treat enteric infections and provide insight into the pathogenesis of chronic inflammatory diseases of the gut. We hypothesize that when SI GAPs are inhibited, other pathways take over driving the development and/or expansion of Th17 cells specific for dietary, microbial, and/or self antigens, which shifts the tone of the immune system to provide enhanced protection during enteric infection and/or injury.

Current Grant Support

R01-AI162918 Edelson/Hsieh (MPI) 2022-2027
Role of Intestinal Parasites on Regulating Immune Responses to Gut Antigens.

R01 AI165771 Wu/Hsieh (MPI) 2022-2027
CAR-T cell treatment of CNS Autoimmunity.

121 AI171994 Wu/Hsieh (MPI) 2022-2024
B cell-targeted CAR-T treatment of CNS Autoimmunity

U01-AI163073 Newberry/Hsieh (MPI) 2021-2026
Gut Intrinsic Inflammatory Responses

R01-AI136515 Hsieh/Newberry (MPI) 2018-2023
The Role of Route of Entry by Bacterial Antigens on Colonic T Cell Reponses


Chyi-Song Hsieh, MD, PhD

Yi J, Miller AT, Archambault AS, Jones AJ, Bradstreet TR, Bandla S, Hsu YS, Edelson BT, Zhou YW, Fremont DH, Egawa T, Singh S, Wu GF, Hsieh CS. Antigen-specific depletion of CD4 T cells by CAR T cells reveals distinct roles of higher and lower affinity TCRs during autoimmunity (2022). Science Immunology, in press.

Russler-Germain EV, Jung J, Miller AT, Young S, Yi J, Wehmeier A, Fox LE, Monte KJ, Chai JN, Kulkarni DH, Funkhouser-Jones LJ, Wilke G, Durai V, Zinselmeyer BH, Czepielewski RS, Greco S, Murphy KM, Newberry RD, Sibley LD, Hsieh CS. Commensal Cryptosporidium colonization drives cDC1-dependent intestinal Th1-mediated homeostasis (2021). Immunity 54(11):2547-2564. PMCID: PMC8716016

Russler-Germain EV, Yi J, Young S, Nutsch K, Wong HS, Ai TL, Chai JN, Durai V, Kaplan DH, Germain RN, Murphy KM, Hsieh CS. Gut Helicobacter Presentation by Multiple Dendritic Cell Subsets Enables Context-Specific Regulatory T Cell Generation (2021). eLife 10:e54792. PMCID: PMC7877908

Hsieh CS, Rengarajan S, Kau A, Tarazona-Meza C, Nicholson A, Checkley W, Romero K, Hansel NN. Altered IgA Response to Gut Bacteria Is Associated with Childhood Asthma in Peru (2021). J Immunol. 207(2):398-407. PMID: 34193598; PMCID: PMC8516662.

Rengarajan S, Knoop KA, Rengarajan A, Chai JN, Grajales-Reyes JG, Samineni VK, Russler-Germain EV, Ranganathan P, Fasano A, Sayuk GS, Gereau IV RW, Kau AL, Knights D, Kashyap PC, Ciorba MA, Newberry RD, Hsieh CS. A potential role for stress-induced microbial alterations in IgA-associated irritable bowel syndrome with diarrhea (2020). Cell Reports Med. 1: 100124. PMCID: PMC7659537

Rengarajan S, Vivio EE, Parkes M, Peterson DA, Roberson EDO, Newberry RD, Ciorba MA, Hsieh CS. Dynamic immunoglobulin responses to gut bacteria during inflammatory bowel disease (2020). Gut Microbes 11:405.

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Current Investigators