Date of Award

5-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Microbiology, Immunology, and Biochemistry

Research Advisor

Hongbo Chi, Ph.D.

Committee

Elizabeth A. Fitzpatrick, Ph.D. Terrence L. Geiger, MD, Ph.D. Thirumala-Devi Kanneganti, Ph.D. Tony N. Marion, Ph.D.

Abstract

Regulatory T (Treg) cells suppress CD4+ T cell responses during homeostasis and inflammation to prevent autoimmunity and other immune disorders. Although the transcriptional and epigenetic programs impacting Treg cell function have been extensively studied, the signaling and metabolic pathways underlying Treg stability and function are not fully understood. In this study, we determined the role of the phosphatase PTEN in Treg cells. We found that specific depletion of PTEN in Treg cells results in excessive TH1 and T follicular helper cells (TFH) responses, associated with elevated germinal center (GC) B cells and spontaneous development of autoimmune and lymphoproliferative disease in vivo. Interestingly, the exaggerated TFH and GC responses and autoimmune symptoms are suppressed when IFN-γ expression is abrogated in mice containing Pten-deficient Treg cells. Thus, the uncontrolled TH1-mediated inflammation in these mice drives aberrant TFH responses and autoimmune and lymphoproliferative disease. Mechanistically, we linked PTEN to mTORC2-mediated control of transcriptional and metabolic programs that enforce Treg cell stability and function. Consistent with this notion, deletion of Rictor, the obligate component for mTORC2, restores Treg cell function and stability in the absence of Pten. Similarly, partially restoring the activity of Foxo1, a downstream transcription factor negatively regulated by mTORC2 signaling, also largely rectified the defects of PTEN-deficient Treg cells. Together, these results establish that Treg cells rely on the PTEN-mTORC2-Foxo1 axis to maintain their stability and suppressive activity in controlling TH1 and TFH cell responses.

ORCID

http://orcid.org/0000-0002-5878-0076

DOI

10.21007/etd.cghs.2016.0400

Available for download on Saturday, June 23, 2018

Share

COinS