# Analysis of peripheral tolerance in vivo

> **NIH NIH P01** · UNIVERSITY OF MINNESOTA · 2020 · $376,174

## Abstract

Project Summary/Abstract
Autoimmune disease often occurs because CD4+ T cells do not become tolerant to major histocompatibility
complex II-bound peptides from the host’s proteins (self p:MHCII). The textbook view is that immature
thymocytes with high affinity TCRs for self p:MHCII complexes displayed by thymic antigen-presenting cells
undergo apoptosis or become suppressive regulatory T (Treg) cells. This mechanism applies to self p:MHCII
generated from proteins that are expressed by thymic antigen-presenting cells naturally, or ectopically under
the control of the AutoImmune Regulator transcription factor. Some self p:MHCII complexes are thought to be
displayed in the secondary lymphoid organs but not the thymus and are tolerated because mature T cells with
high affinity TCRs become anergic. Although this is an elegant theory, it has not been validated because a
natural population of polyclonal T cells that becomes anergic in the extra-thymic tissues of normal individuals
as a consequence self p:MHCII recognition has not been identified. Here, we will test the hypothesis that the
newly discovered population of Foxp3− FR4high CD73high T cells is the natural anergic population. We will
determine whether these cells become anergic via persistent stimulation by self p:MHCII complexes that are
displayed in secondary lymphoid organs but not the thymus and can regain some degree of responsiveness
under hyper-inflammatory conditions and participate in organ-specific autoimmunity. This project could provide
the best evidence to date that T cell anergy is a physiological tolerance mechanism and identify the types of
self epitopes that it protects the host from. It could validate or rewrite the textbooks and be of applied value by
improving understanding of how tolerance fails during autoimmune disease.

## Key facts

- **NIH application ID:** 9994828
- **Project number:** 5P01AI035296-26
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Marc Kevin Jenkins
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,174
- **Award type:** 5
- **Project period:** 1997-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994828

## Citation

> US National Institutes of Health, RePORTER application 9994828, Analysis of peripheral tolerance in vivo (5P01AI035296-26). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9994828. Licensed CC0.

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