# Regulating peripheral T cell tolerance

> **NIH NIH R56** · DUKE UNIVERSITY · 2020 · $309,442

## Abstract

Summary of Work/Abstract
 Autoantibodies are pivotal for the pathogenesis of many autoimmune diseases such as system lupus
erythematosus (SLE). T follicular helper cells (Tfh) cells are important players in both normal immune
responses and autoimmune disease via contact dependent and independent mechanisms to provide helping
signals to B cells in the germinal centers (GCs). Tfh cells promote GC B cell proliferation and survival, Ig class
switch and affinity maturation, and memory B cell and plasma cell formation. However, deregulated Tfh can
trigger abnormal GC B and memory B cell responses to produce autoantibodies and contribute to autoimmune
diseases. Tregs, particular Tfr, suppress Tfh cells and GC responses and are critical for prevent autoimmune
diseases. Abnormal Tfh and Tfr cells have been associated with or are the causal factors of autoimmune
diseases in human patients and/or in autoimmune mouse models. However, the origin of pathogenic Tfh cells
in autoimmune diseases has been elusive. Diacylglycerol (DAG) is a critical second messenger that relays
proximal signal from the TCR to downstream pathways such as RasGRP1-Ras-Erk1/2 and PKCθ-IKK-NFκB
pathways as well as PI3K-mTOR signaling. DAG kinases (DGKs) α and ζ terminate DAG signal by conversion
to phosphatidic acid. Our preliminary studies with Treg-specific DGKα and ζ double deficient mice have
revealed critical roles of these enzymes for proper function and stability of Tregs to maintain self-tolerance and
to prevent autoimmune diseases. Building strong preliminary data, we will test the novel hypotheses that
deregulated conversion of Treg/Tfr to exTreg-Tfh cells is a major source of pathogenic self-reactive Tfh cells
that trigger deregulated GC and autoantibody responses that lead to autoimmune diseases and that DGKα
and ζ serve as a checkpoint to brake the conversion. The proposed studies are expected to improve
understanding of the mechanisms that control Treg stability and function and to illustrate the origins of
pathogenic self-reactive Tfh cells, and provide novel understanding for the pathogenesis and treatment of
autoimmune diseases.

## Key facts

- **NIH application ID:** 10125705
- **Project number:** 2R56AI079088-10
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** XIAOPING ZHONG
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $309,442
- **Award type:** 2
- **Project period:** 2008-05-13 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10125705

## Citation

> US National Institutes of Health, RePORTER application 10125705, Regulating peripheral T cell tolerance (2R56AI079088-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10125705. Licensed CC0.

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