Defining how TCR strength of signal modulates Treg function

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Abstract/Summary Millions of people worldwide have been diagnosed with autoimmune diseases such as multiple sclerosis (MS). The hallmark of MS is progressive demyelination driven by an inappropriate immune response that attacks cells within the central nervous system. The dominant risk factor for MS, and experimental autoimmune encephalomyelitis (EAE) animal models, in addition to many other autoimmune diseases (type I diabetes, rheumatoid arthritis, etc) is specific MHC class II molecules. Since MHC class II presents peptide antigen to both CD4+ T conventional (Tconv) and regulatory T cells (Tregs), the interaction between the T cell receptor (TCR) and self peptide:MHC (pMHC) plays a pivotal role in autoimmune disease progression. The vital purpose of Tregs is to suppress immune responses against self in an antigen specific manner. Tregs recognize antigen such as myelin via their TCR, yet the fundamental measures and the underlying mechanism of TCR interaction with pMHC is unknown. Therefore, a thorough understanding of the antigen-specific reactivity of Tregs and whether this activity could be exploited has significant therapeutic potential. Here, we will dissect the interaction between TCR and myelin antigen using sensitive technologies to measure biophysical properties of TCR binding such as affinity and bond lifetimes. Of note, Tregs apply force to the bond between TCR and pMHC, which is ultimately reflected by changes in how long the proteins interact. While Treg TCRs are said to have enhanced strength of signal, mechanistically this concept is poorly defined. We discovered that suppressive Tregs apply more force to the pMHC bond than do Tconv cells. In addition, myelin-specific Tregs that fail to suppress apply lower levels of force. We therefore hypothesize that during antigen recognition, the increased magnitude of force determines the Treg suppressive phenotype. We have designed three aims to test this hypothesis that will: 1) compare antigenic binding parameters of functional versus defective Tregs; 2) determine Treg functional parameters dependent on the magnitude of force; and 3) engineer TCR sequences to decouple affinity, bond lifetime, and the level of force in response to self antigen. Thus, our project will provide novel insight into the mechanisms governing Treg function and dysfunction during demyelinating autoimmune disease. Our work will be the first to investigate various levels of force as a potent biomarker for Treg that dictates their suppressive efficacy, potency, and phenotypic stability.