CD200 Expression on Apoptotic DCs and Immune Tolerance

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DESCRIPTION (provided by applicant): During apoptotic cell death, biochemical processes, including the action of caspases, modify self-proteins and create potential autoantigens. To maintain a steady-state in the face of natural cell turnover, the immune system must have a mechanism to prevent or control responses to cell death-associated autoantigens or risk autoimmunity. CD200 is a transmembrane glycoprotein that shares sequence homology with the B7-family of T cell costimulatory molecules and is known to impart a T cell tolerogenic signal. We made the novel observation that CD200 mRNA and protein expression was increased in apoptotic murine dendritic cells (DCs). We identified functional p53-response elements within the CD200 gene. We identified both p53- and caspase-dependent pathways leading to increased expression of CD200 on apoptotic DCs. CD200 on apoptotic DCs significantly altered the rate of T cell proliferation and the cytokine profile in autologous MLR cultures. Furthermore, using CD200 knockout mice, we found that CD200 was essential for induction of UVB-mediated immune tolerance to haptenated proteins in contact hypersensitivity assays. Based on our mouse data, we hypothesize that CD200 expression on apoptotic DCs contributes to the induction of immune tolerance to caspase-generated self-peptides in vivo. We propose to test this hypothesis in vivo using an established mouse model of immune tolerance to hapten and to extend our studies to human DCs and immune responses to both caspase-generated self-peptides and model autoantigens in vitro. Our Specific Aims are: (1) To determine whether CD200 on infused or resident DCs plays a role in the induction of immune tolerance to hapten using wild-type and CD200 knockout mice; (2) To assess the expression of CD200 mRNA and protein in subsets of human DCs and in cultures of primary keratinocytes with and without induction of apoptosis; and (3) To test the effect of blocking CD200/CD200R interaction on T cell responses to caspase-generated self-peptides, nucleohistone and myelin basic protein using PBMC from normal individuals and multiple sclerosis patients. If the data support our hypothesis, we will have identified CD200 expression on apoptotic DCs as an important molecule in maintaining self-tolerance in humans and, perhaps, in limiting autoimmunity. These studies will also provide new insight into a novel molecular pathway that is a target for enhancement of antitumor immunity and for prevention of graft rejection.