The development of both tolerance and autoimmunity is dependent on the presentation of self-antigens in the thymus and periphery. Thymic tolerance requires recognition of self-antigens leading to negative selection, i.e. deletion of self-reactive T cell clones; or selection into Foxp3+ regulatory T (Treg) cells, important for maintaining immune homeostasis in the periphery. In the periphery, presentation of self-antigens results in maintenance and induction of regulatory T cells to promote tolerance, but can also facilitate autoimmunity via induction of self-reactive effector cells. These processes are driven by antigen presenting cells (APCs), of which there are several subsets. Previously, we showed that Batf3-dependent CD8?+ DCs play an important role in thymic tolerance as the major recipient of antigen transfer from medullary thymic epithelial cells (mTECs), which produce a variety of self-antigens via the effect of the transcription factor Aire. Here, we propose to continue our studies on the role of CD8?+ DCs in tolerance and autoimmunity. We will continue our ongoing studies of thymic CD8?+ DCs with the goal of understanding the mechanisms of antigen transfer (Aim 1). We will also ask whether CD8?+ DCs present a unique array of self-antigens in the periphery with the goal of identifying the origin of some of these antigens (Aim 2). Finally, we will determine whether peripheral CD8?+ DCs are involved in effector vs regulatory T cell differentiation in response to self-antigens (Aim 3). If successful, this grant will offer new insights regarding the role of CD8?+ DCs in providing antigen-specific and T cell developmental niches in the thymus and periphery that may control the balance between tolerance and autoimmunity.
Autoimmune disease is an important clinical problem, and may affect up to 50 million Americans. For many of the diseases, a loss of T cell tolerance to self-antigens is thought to play a role. The goal of this study is to understand the basic mechanisms of how T cells in the body learns tolerance to self in the thymus as T cells are developing, and in the rest of the body after they mature. Knowledge of these mechanisms may facilitate the development of novel treatments or diagnostic tests for autoimmune disease.
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