Regulatory T cells (Tregs) are critical for proper control of the immune response and play a clear role in regulation of autoimmune disease. Further highlighting their importance, Tregs provide an antigen specific therapy that is currently being evaluated in preclinical and clinical trials. Although they are of unquestioned value, it is difficult to assess Treg specificity for antigen. In fact, many experimental protocols make use of non-specific TCR stimuli such as anti-CD3/anti-CD28 for their activation, and typical assessments of specificity such as peptide: MHC Class II tetramers and functional readouts are not especially effective when applied to Tregs. As TCR specificity and affinity are crucial to any T cell functional response, we need to understand what affinity range works best for optimal Treg use as well as for their differentiation. Our lab is in a unique position to examine questions on TCR specificity and affinity because we have developed a novel assay system based on two dimensional (2D) micropipette technology that provides the most sensitive means currently available to assess these parameters. The prevalent view of thymic derived Tregs (tTreg) in terms of affinity is that their repertoires are comprised of the highest affinity TCRs that escaped negative selection; however, our preliminary data has identified a range of affinities of tTregs specific for myelin oligodendrocyte glycoprotein (MOG). Instead of driving thymocyte negative selection, MOG supports development of thymic derived MOG specific Tregs. We propose that these Tregs will be of therapeutic use and based on our preliminary studies, propose the following two aims to track Treg specificity, location, kinetics, stability, and potency during chronic and relapsing/remitting demyelinating disease.
Aim 1 : To define MOG-specific Treg affinity and frequency during demyelinating disease- Aim 2: To determine Treg specificity and lineage stability for MOG-

Public Health Relevance

Regulatory T cells control the extent of adaptive immune responses, are crucial for the prevention of autoimmune diseases, and play a defined role in human health. Our studies will address a currently unmet need by determining Treg affinity and specificity for myelin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI110113-03
Application #
9171945
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ramachandra, Lakshmi
Project Start
2014-12-01
Project End
2019-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Emory University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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