Biophysical and structural basis of T cell selection at the intersection of the conventional and regulatory T cell repertoires

About This Grant

Project Summary/Abstract Autoimmune disease affects one in twenty people in the United States, representing a significant health burden. The pathogenesis of many human autoimmune diseases is dependent on CD4+ T cells, which recognize short peptide antigens complexed with host MHC class II (pMHC-II) molecules by means of a unique, clonally arranged αβ T cell receptor (αβTCR). Some developing T cells rearrange αβTCRs that react strongly with endogenous self-pMHC-II and have the potential to induce autoimmunity. To combat this, some self-reactive T cells are purged by clonal deletion or directed into the Foxp3+ regulatory T (Treg) cell lineage. However, these processes are imperfect, leading to the escape of some self-pMHC-II-reactive clones into the peripheral conventional T (Tconv) cell repertoire. Notably, the control of such clones in the periphery requires continuous extrinsic constraint by Foxp3+ Treg cells. Thus, the peripheral pool of self-reactive CD4+ T cells sits at the nexus of autoimmunity and tolerance, harboring both the self-pMHC-II-reactive Tconv cells capable of triggering autoimmunity and the broad pool of self-reactive Treg cells required to control them. The objective of this application is to define the biophysical and structural basis of self-pMHC-II recognition by αβTCRs expressed by Tconv and Treg cells of shared antigen specificity, and define how these features impact T cell fate and function in the thymus, periphery, and autoimmune target organ. We will achieve our objectives by testing the central hypothesis that the degree to which a TCR is centered over self-pMHC-II serves as a critical determinant of TCR signaling sensitivity, favoring interactions of higher stability while simultaneously facilitating optimal engagement of MHC-II by the CD4 coreceptor. In Aim 1, we will define the biophysical and structural basis of self-pMHC-II recognition by TCRs expressed by Treg and Tconv cells of shared specificity. In Aim 2, we will define the in vivo differentiation trajectories and autoimmune functional potential of self-pMHC-II reactive clones expressing TCRs exhibiting variable antigen-binding features. Upon completion of this work, the data will provide insights into self- reactive CD4+ T cells at both ends of the tolerance/autoimmunity spectrum. First, we will gain much-needed knowledge regarding the biophysical and structural basis of self-pMHC-II recognition by Treg cells, which are required throughout life for the prevention of autoimmunity. Second, we will define the antigen-binding features of self-pMHC-II Tconv cells that have optimal potential to breach immune tolerance and drive autoimmunity. Bridging these two objectives, comparative analyses will define the extent to which the features of self-pMHC-II by Treg cells differ from those of Tconv cells reactive to the same self-pMHC-II. These goals directly align with the mission of the NIH and NIAID to produce fundamental knowledge about living systems and apply that knowledge to improve human health outcomes, specifically in debilitating autoimmune conditions, which represent a significant and expanding health burden in the United States.