Tolerance to self-antigens is maintained at multiple levels. While central tolerance is essential to preventing autoimmunity, autoreactive T and B cells nevertheless are present in the peripheral repertoire. Thus, peripheral tolerance to tissue-specific and developmentally regulated antigens is necessary to sustain tissue homeostasis. In some cases, cross-reactive memory cells produced by infection are likely to be responsible for autoimmunity via recognition of self-antigens in the context of ongoing inflammatory events. We have now devised an inducible and reversible system that allows interrogation of T cell tolerance induction in endogenous memory CD8 T cells. Our data show that memory CD8 T cells responded poorly to self-antigen even when expressed by dendritic cells (DC) and despite the fact that the antigen was readily recognized by na?ve CD8 T cells. However, the inclusion of inflammatory signals partially overcame memory CD8 T cell ignorance of self-antigen. Thus, memory CD8 T cells were prohibited from autoreactivity in the absence of inflammation. These results led to the hypothesis that tolerance is maintained by disallowing memory CD8 T cell recognition of self antigen under homeostatic conditions. Our goal is to determine the mechanism by which memory CD8 T cells ignore direct DC antigen presentation and test whether tissue-specific antigens are also ignored. This goal will be achieved through two specific aims:
Aim 1. To determine the anatomical constraints prohibiting memory CD8 T cell recognition of DC-expressed antigen.
Aim 2. To determine whether memory CD8 T cells will recognize cross-presented tissue-specific antigen in the absence of inflammation. Our new system will provide a powerful tool for identifying the mechanisms by which autoimmunity may be avoided or controlled.

Public Health Relevance

Understanding how autoreactive T cells are triggered to respond to self-antigens is at the heart of learning how to control autoimmune diseases. This proposal focuses on the regulation of self-antigen recognition by cytotoxic memory CD8 T cells. Therefore, this work will provide valuable insight into the mechanisms controlling autoreactivity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI109188-02
Application #
8890780
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Rothermel, Annette L
Project Start
2014-07-11
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code