Figure 1. Proposed mechanisms of tolerance induced by antigen-coupled apoptotic cells and Ag-coupled PLG nanoparticles.

Intravenous infusion of Ag-coupled ECDI-fixed apoptotic cells or Ag-coupled biodegradable PLG nanoparticles enter 'tolerogenic' APCs in the spleen and liver via scavenger receptors, e.g. MARCO [27, 54]. Uptake leads to presentation of the coupled Ag by MHC molecules on the host splenic and liver APCs. Concomitantly, signals resulting from the scavenger receptor uptake cause upregulation of regulatory costimulatory molecules, e.g. PD-L1/2 without upregulation of positive costimulatory molecules, e.g. CD80 and CD86, as well as the production of IL-10 and TGF-β [27]. A. Host tolerogenic APCs induce anergy/apoptosis in activated antigen-specific T cells via engagement of PD-1 which is upregulated on activated T cells [27, 60-62]. B. Host tolerogenic APCs induce anergy in naive antigen-specific T cells by presenting cognate Ag/MHC in the absence of positive costimulatory interactions (i.e. signal one in the absence of signal 2) [21]. C. PD-L1 expressing, IL-10-producing host tolerogenic APCs induce the induction/expansion of antigen-specific induced regulatory T cells (Tregs)/Tr1 cells, which synergistically act to regulate the differentiation of naive T cells to become pathogenic effector T cells, and which regulate the effector function/trafficking of activated pathogenic T cells [27, 60, 63, 64].