It is now widely appreciated that gut commensal bacteria play a major role in health and disease. While dysregulation of the intestinal flora has been shown to contribute to many autoimmune abnormalities, specific relationships between particular microbial species and the state of host immunity have been unraveled for only a small number of organisms. Recent studies have supported the notion that segmented filamentous bacterium is a key gut commensal bacterium for driving mucosal Th17 responses, which is arguably one of the most exciting discoveries in the field. However, there exist intense debates on key aspects of the development of mucosal Th17 cells. Taking advantage of unique tools recently developed, we aim to address three important questions: (1) Which cytokines are required for SFB-specific Th17 cell induction; (2) What are the specific mucosal APC subsets that present bacterial antigens; and (3) How does antigen affinity of TCRs impact on Th17 differentiation. The feasibility of this proposal is supported by (1) many unique tools that we developed, including CD4 T cell hybridomas, novel TCR transgenic mice and transgenic Listeria monocytogenes; and (2) our first-hand experience in mucosal immunology in general and with this experimental system in particular. Insights to be derived from this project will be important for understanding and harnessing mucosal immune responses.

Public Health Relevance

T helper-17 (Th17) cells are uniquely dependent on intestinal microbial colonization for their differentiation. These cells are involved in mucosal defenses and autoimmune diseases, and they hold great promise for cancer immunotherapy. A detailed understanding of how Th17 cells develop in the gastrointestinal mucosa will lead us to new commensal specific interventions to treat and prevent disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AI125859-01
Application #
9169816
Study Section
Special Emphasis Panel (ZAI1-ALW-I (M1))
Program Officer
Rothermel, Annette L
Project Start
2016-06-21
Project End
2021-05-31
Budget Start
2016-06-21
Budget End
2017-05-31
Support Year
1
Fiscal Year
2016
Total Cost
$523,250
Indirect Cost
$173,250
Name
Medical University of South Carolina
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403
Hong, Feng; Mohammad Rachidi, Saleh; Lundgren, Debbie et al. (2017) Mapping the Interactome of a Major Mammalian Endoplasmic Reticulum Heat Shock Protein 90. PLoS One 12:e0169260
Hua, Yunpeng; Yang, Yi; Sun, Shaoli et al. (2017) Gut homeostasis and regulatory T cell induction depend on molecular chaperone gp96 in CD11c+ cells. Sci Rep 7:2171
Ansa-Addo, Ephraim A; Zhang, Yongliang; Yang, Yi et al. (2017) Membrane-organizing protein moesin controls Treg differentiation and antitumor immunity via TGF-? signaling. J Clin Invest 127:1321-1337
Rachidi, Saleh; Metelli, Alessandra; Riesenberg, Brian et al. (2017) Platelets subvert T cell immunity against cancer via GARP-TGF? axis. Sci Immunol 2:
Thaxton, Jessica E; Wallace, Caroline; Riesenberg, Brian et al. (2017) Modulation of Endoplasmic Reticulum Stress Controls CD4+ T-cell Activation and Antitumor Function. Cancer Immunol Res 5:666-675
Metelli, Alessandra; Wu, Bill X; Fugle, Caroline W et al. (2016) Surface Expression of TGF? Docking Receptor GARP Promotes Oncogenesis and Immune Tolerance in Breast Cancer. Cancer Res 76:7106-7117
Hong, Feng; Liu, Bei; Chiosis, Gabriela et al. (2013) ?7 helix region of ?I domain is crucial for integrin binding to endoplasmic reticulum chaperone gp96: a potential therapeutic target for cancer metastasis. J Biol Chem 288:18243-8