# Mechanisms of Disease Pathogenesis in Regulatory T cell Deficiency

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $424,768

## Abstract

Foxp3+ regulatory T (TR) cells are pivotal to the maintenance of peripheral immunological tolerance. This
complex population includes the “natural” TR (nTR) lineage that develops in the thymus and the comparatively
unstable “induced” TR (iTR) cells that arise from conventional T cells in the periphery. Loss of function Foxp3
mutations in humans and in mice give rise to TR cells lacking in regulatory activities, resulting in fatal
autoimmunity. In Foxp3-sufficient hosts, instability of Foxp3 expression in iTR cells, especially under
inflammatory conditions, gives rise to Foxp3-deficient ex-iTR cells that are pathogenic. Foxp3 deficient TR cells
continue to express core elements of the canonical TR transcriptional signature. However, they also acquire a
phenotype and transcriptional profile similar to terminally differentiated effector T (TEff)-like cells. They switch
their energy metabolism to aerobic glycolysis, exhibit mTORC1 and mTORC2 activation and produce Th1, Th2
and Th17 cytokines that contribute to systemic inflammation. The molecular mechanisms mediating the
acquisition by Foxp3-deficient TR cells of a TEff phenotype and the abrogation of their suppressive function
remain obscure. To elucidate these mechanisms, we have created a novel mutant Foxp3 allele (Foxp∆EGFPiCre)
that simultaneously abrogates expression of Foxp3 while driving the expression of a humanized Cre
recombinase (iCre) fused with an enhanced green fluorescent protein (EGFP). We demonstrate that
Foxp∆EGFPiCre TR (ΔTR) cell-specific deletion of Rictor, which encodes an essential component of the mammalian
target of Rapamycin complex 2 (mTORC2), substantially ameliorates the disease associated with Foxp3
deficiency. Rictor deletion in ΔTR cells restores nuclear Foxo1 localization, suppresses Th1 programing,
inhibits aerobic glycolysis, and partially rescues regulatory activity. Accordingly, we hypothesize that TR cell
failure due to genetic or acquired Foxp3 deficiency is driven by the dysregulation of a limited but critical set of
molecular pathways, including the mTORC2/AKT/Foxo1 axis and metabolic regulators of aerobic glycolysis,
that together oversee the transformation of the ΔTR and ex-TR cells into TEff -like cells. In this proposal, we will
examine the mechanisms by which dysregulation of these pathways impair ΔTR cell function. We will then use
mTORC2/AKT/Foxo1 axis inhibition and metabolic reprogramming to improve the stability and function of iTR
cells in TR-cell based treatment models of autoimmune disease. The proposed experiments will elucidate the
pathogenesis of autoimmune or dysregulatory diseases stemming from genetic or acquired loss of Foxp3
expression. Critically, they will enable the creation of new therapies designed to rescue the regulatory activity
of dysfunctional TR cells. Such therapeutic approaches are eminently applicable to boosting TR cell function in
common disease states that include autoimmunity and graft versus host disease.

## Key facts

- **NIH application ID:** 9984930
- **Project number:** 5R01AI085090-10
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Talal Amine Chatila
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $424,768
- **Award type:** 5
- **Project period:** 2010-08-30 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984930

## Citation

> US National Institutes of Health, RePORTER application 9984930, Mechanisms of Disease Pathogenesis in Regulatory T cell Deficiency (5R01AI085090-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9984930. Licensed CC0.

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