Autoimmunity is defined by the inability of the immune system to differentiate between healthy body tissue and foreign antigens, thereafter inducing a heightened immune reaction to normal body tissues it would normally ignore. During thymocyte development, T cells undergo a selection process based on the avidity of their individual T cell receptor (TCR) to the self-ligand/major histocompatibility complex (MHC) presented by thymic antigen presenting cells. T cells that express TCRs with strong avidity to self are usually filtered out during this process by negative selection in order to remove potentially hazardous autoreactive T cells. We have recently made a novel observation that in addition to TCR signal, a cohort of molecules, such as CD5, CD6, GITR and CD26 alter the TCR signal potential and contribute to establishing a diverse T cell repertoire. These 'fine-tuning molecules work together in symmetry to establish a signaling threshold during T cell selection, as suggested in our studies using knockout for a set of these molecules. Guided by this novel finding, we posit that a mis-regulation of these molecules results in a positive selection and hypersensitivity of T cells, which contributes to the development of autoimmune disorders. Moreover, preliminary evidence suggests that these molecules continue to be tuned in the periphery and may contribute to T cell hyper-reactivity. We will begin to test this idea in this exploratory proposal. We will begin by analyzing the differential expression of the top twenty candidate 'fine-tuning'molecules in thymic and peripheral T cells of autoimmune mouse models. Using the activating or neutralizing antibodies for the five most differentially expressed molecules, we will determine the function of these 'fine-tuning'molecules in affecting the signaling threshold in autoimmune and normal T cells. We will then determine whether modulating the expression of these molecules (top two candidates in this exploratory grant) in autoimmune T cells will restore normal T cell activation and homeostasis. This study has the potential to reveal autoreactive T cell markers that may serve as early biomarkers as well as candidate therapeutic targets to treat autoimmune pathologies.
This proposal will translate knowledge gained from our thymocyte development studies to investigate mechanisms of autoimmune diseases that afflict more than 5% of world population and cause substantial morbidity and mortality. There is no optimum therapy for these diseases. The knowledge gained from the proposed studies has potential to screen for autoimmune disease predisposition as well as to identify new targets for treatment.