Deciphering the specificity and molecular mechanisms of regulatory T cells using novel approaches

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Project Summary: Autoimmunity is a leading cause of chronic illness that encompasses more than 80 individual diseases. Due to the rising prevalence of these diseases, autoimmunity associated health problems currently affect over 20 million individuals only in the USA, constituting a health crisis that requires immediate attention. Autoimmune diseases stem from disturbances in the tolerance of immune system against self-tissues. Immune tolerance is achieved in part by the elimination of self-reactive T cells during their development in the thymus. The self-reactive clones that escape thymic elimination are actively silenced in the periphery by a subset of T cells called “regulatory” T (Treg) cells. Because Treg defects result in fatal autoimmunity, increasing Treg number and activity in the body appears to be a desirable strategy to prevent and treat autoimmune diseases. However, we have a major gap in our understanding of how Tregs perform their inhibitory roles at the molecular level and this hinders the development of effective therapeutic strategies. Recently, I demonstrated, for the first time, that Tregs can inhibit effector T cells in an antigen-specific manner. I reported that Treg antigen receptor (TCR) can remove class II major histocompatibility complex bound antigenic peptide (pMHCII) from surface of antigen presenting cell (APC), dendritic cell (DC) in particular, thus deplete the antigenic stimulus that effector T cell needs to receive to get activated. I revealed that this happens during Treg-Dendritic cell (DC) contact, whereby cognate pMHCII laden DC membrane is captured by Treg in an elegant way that does not reduce the presentation of non-cognate pMHCII by the same DC. I hypothesize that this highly specific mechanism can be exploited to effectively reduce pathological presentation of self-antigen by APC as a promising strategy to combat autoimmunity. I will test this hypothesis by taking the following steps: 1) Determining the antigen specificity of Treg suppression and pMHCII removal in human Tregs and visualizing their interactions with DCs that present self-antigens. 2) Characterizing the molecular machinery employed by Tregs to perform pMHCII depletion and dissect the molecular switches that can be targeted to tune Treg activity. 3) Determining the functional significance of antigen capture by Tregs to reveal potential mechanisms whereby Tregs present captured pMHCII complexes to prime naive T cells resulting in the spreading of antigen specific tolerance. By uncovering novel pathways of antigen-specific immune suppression, this New Innovator Award will identify new targets for immune system modulation that can be utilized for the treatment of chronic diseases such as autoimmunity and cancer. Findings from this project will be instrumental in generating future antigen-targeted immunotherapies, thus the objectives of this New Innovator Award serve the strategic mission of the National Institute of Allergy and Infectious Diseases.