Dendritic cells (DCs) are potent antigen presenting cells (APC) that play a central role in the induction of immunity and tolerance. In the steady state, DCs in peripheral tissues acquire self-antigens by phagocytosing neighboring cells that are undergoing apoptosis, as a result of physiologic cell turnover. Following migration to draining lymph nodes, DCs elicit self-antigen-specific, but tolerogenic responses from CD4+ and CD8+ T cells. Much remains to be learned about the events that distinguish the induction of tolerance vs. immunity during the cross-presentation of antigens derived from apoptotic cells (AC). For example, the hierarchy of AC receptors utilized by human DCs is unknown. We have shown that individual ligation of two such receptors, CR3 and CR4, inhibits human DC maturation, down modulates their immunostimulatory activity and leads to the abrogation of T cell responses. Therefore, by targeting CR3 and CR4 on DCs, AC can turn off self-reactive T- cell responses in the steady state. In this proposal, we plan to exploit AC receptors to induce tolerogenic human DCs. In the first aim we will assess the contribution of CR3 and CR4 towards TDC induction by using siRNA to block their expression in immature DC. Binding and phagocytosis of AC as well as immunostimulatory function will be evaluated. Secondly, we will identify the mechanism by which T cell tolerance is induced (deletion, anergy, and/or induction of regulatory T cells). In the second aim, we propose to identify relevant molecules and signaling pathways that lead to the induction of tolerogenic DCs (TDC). Advantage will be taken of the AC surrogate system to identify which signaling pathways are used by AC receptors on human DCs. The information gained will lead to a better understanding of TDC development and potentially, novel approaches for their generation ex vivo.
The third aim will focus on developing animal models to test the tolerizing activity of AC receptor ligated DCs. We will (i) test whether CR3/4 ligated DCs induce tolerance to the model antigen OVA, and (ii) determine the nature of the tolerance induced (anergy, deletion and/or T regulatory cells). In the fourth aim, we will determine whether engagement of AC receptors on DC from patients with autoimmunity (Systemic Lupus Erythematosus) imparts them with tolerogenic properties. The goal is to take advantage of the selective effects of CR3/4 signaling to develop TDC with the capability of down-modulating autoimmune T cell responses. The information gained may lead to novel, physiologically relevant approaches that can be translated rapidly into the clinic to treat auto-immune disease.
The prototypic autoimmune disease Systemic Lupus Erythematosus (SLE) is a multi-system disease manifested by lesions in the skin, kidney, and other organs. There remains no cure for the disease, which is considered to arise because of a prominent autoreactive response to self-antigens. The overall goal of this application is to develop physiologically relevant immunotherapies that can be used to treat SLE. The studies described will make use of novel approaches identified in our laboratory to suppress ongoing autoimmunity.
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