Peripheral T cell tolerance versus autoimmunity Is determined by dendritic cell presentation of antigen. Our prior work, using foreign antigens, has shown that antibody-mediated enhancement of antigen presentation by dendritic cells induces potent effector CD8 responses in vivo, in a manner regulated by the opposing actions of the activating and inhibitory Fc receptors. Our preliminary work using a model self-antigen, has shown that autoantibody potently induces autoreactive T cell activation to islet cell antigens in vivo. Neither islet-specific CD8 T cells nor autoantibodies alone are sufficient to induce diabetes, however together antibodies and T cells induce disease synergistically. Autoantibodies to islet cell antigens are found prior to clinical onset of IDDM. Yet as with other autoantibodies commonly found in autoimmune states in which T cells are effectors, islet cell antibodies are widely believed to be a marker but not a contributing factor in disease. This is because unlike autoreactive T cells, islet cell antibodies lack intrinsic pathogenicity. Thus the requirement for B cells in diabetes has been interpreted as revealing a role for B cells as APCs. Here we show that dendritic cell uptake of immune complexes potently enhances the activation of auto-aggressive T cells. Thus both B cells and their secreted immunoglobulin products contribute to loss of T cell mediated tolerance via their roles in facilitated antigen presentation. We have identified a novel pathway of autoimmune pathogenesis and subsequently interrupted it using a clinically relevant therapeutic (IVIg). We further show that IVIg attenuates diabetes in this model via inhibitory effects on antigen presentation in vivo. We have established an elegant genetic system to address the mechanism of how autoantibody breaks peripheral T cell tolerance. Using genetic systems a role for both activating Fc receptors and complement have been identified. Experiments in Aims 1 and 2 use OVA as a model antigen and will provide basic knowledge for defining the role of DCs, complement and Fc receptors in triggering the emergence of antibody-triggered autoaggressive T cells and its blockade by IVIg. We propose in Aim 3 to extend this work to test relevance to the antibody-mediated cross-presentation of insulin, an antigen of singular importance to diabetes. ? ? ?
| Flores, Marcella; Chew, Claude; Tyan, Kevin et al. (2015) Fc?RIIB prevents inflammatory type I IFN production from plasmacytoid dendritic cells during a viral memory response. J Immunol 194:4240-50 |
| Colonna, Lucrezia; Catalano, Geoffrey; Chew, Claude et al. (2010) Therapeutic targeting of Syk in autoimmune diabetes. J Immunol 185:1532-43 |
| Harbers, Stephanie O; Crocker, Andrea; Catalano, Geoffrey et al. (2007) Antibody-enhanced cross-presentation of self antigen breaks T cell tolerance. J Clin Invest 117:1361-9 |
| Desai, Dharmesh D; Harbers, Stephanie O; Flores, Marcella et al. (2007) Fc gamma receptor IIB on dendritic cells enforces peripheral tolerance by inhibiting effector T cell responses. J Immunol 178:6217-26 |
