Antigen Presentation and T cell Programming in Human Autoimmune Diseases

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DESCRIPTION (provided by applicant): Antigen presentation is an integral component of every autoimmune disease process, and thus represents an important scientific and clinical problem. The seven investigators who come together in this PPG have highly complementary areas of expertise and have formed a cohesive, multidisciplinary program. The overarching hypothesis is that the development and progression of autoimmune diseases are controlled by specialized populations of antigen-presenting cells (APCs) that serve distinct roles in the induction of different effector and regulatory T cell programs. The team emphasizes direct investigation of APC - T cell interactions in patients with autoimmune diseases, in particular multiple sclerosis (MS), and integrates these human immunological studies with in-depth mechanistic studies in relevant animal models. During the previous funding period, the group developed a novel nanowell-based technology platform for multiplexed investigation of T cell function in autoimmune diseases. The technology enables co-culture of single T cells with mature dendritic cells in wells of subnanoliter volume for multi-dimensional characterization of cytokine secretion and surface markers. Furthermore, responding T cells can be recovered with a robotic device for characterization of transcriptional programs. This technique will be used by all investigators to examine the functional consequences of T cell interactions with distinct populations of APC. The team will address a long-standing challenge in the field and define the functional and molecular differences between self-reactive T cells in patients with MS and healthy subjects. Studies in MS CNS lesions and animal models will examine how the interaction of T cells with different populations of APCs results in the formation of chronic inflammatory microenvironments in the target organ. Of particular interest is the complex interplay between T cells, B cells and stromal cells that results in the formation of ectopic lymphoid follicles in the CNS. Studies during the previous funding period have shown that Th17 cells express podoplanin (PDPN), a surface molecule that interacts with CLEC-2 on B cells and mature dendritic cells. Antibody-based blockade of PDPN function prevents formation of ectopic lymphoid follicles, and the function of these molecules will now be studied in MS lesions and conditional knock-out mice. The program is highly synergistic based on our focus on an important problem in the autoimmunity field, and our highly collaborative approach integrates a unique team of investigators with expertise in molecular and cellular immunology, biophysics, and engineering to investigate disease mechanisms in autoimmunity with cutting-edge technologies.