In the intestine, regulatory T cells that express Foxp3 transcription factor (Tregs) are critical for the regulation of adaptive immune response to commensal antigens. Tregs differentiate in the thymus (tTregs) or convert from naive, peripheral Foxp3- T cells (pTregs).It is currently unclear if tTregs and pTregs have redundant or complimentary role in maintenance of intestinal homeostasis. Our long term goal is to understand how the homeostatic balance in the intestine depends on pTregs and tTregs, and how their TCR repertoires can change by exposure to antibiotics. Our central hypothesis is that clonal expansions and selective trophism of tTregs are essential to sustain intestinal equilibrium. To test our hypothesis we propose two specific aims. First we will characterize TCRs on mucosal Tregs in the intestine of CNS1mut mice that lack pTregs but have normal tTregs. In addition, in these mice CD4+ T cells express semi diverse repertoire of TCRs and activated Tregs express green fluorescent protein (GFP). We hypothesize that in these mice mucosal tTregs will control intestinal nave and effector T cells, and that TCRs expressed by tTregs can be specific to commensal antigens. Second, we will investigate how antibiotic treatment early in life can permanently change microbial flora and clonal diversity of intestinal Tregs. We hypothesize that changes in the diversity for microbial flora induced by neonatal exposure to antibiotics permanently alter repertoire of intestinal tTregs.

Public Health Relevance

The experiments proposed in this application will examine how antigens derived from commensal bacteria influence clonal diversity of regulatory CD4+ cells (Tregs) derived from the thymus (tTregs) or the pepriphery (pTregs). These experiments will be use new strain of mice that express restricted repertoire of TCRs and Foxp3GFP reporter, but lacks TGF? induced pTregs. We also propose to investigate how neonatal expsure to antibiotics alter antigenic specificties of intestinal Tregs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI121151-04
Application #
9606368
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Rothermel, Annette L
Project Start
2016-12-01
Project End
2020-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Georgia State University
Department
Miscellaneous
Type
Organized Research Units
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302