The Modulation of Adaptive Immune Responses by Bacterial Zwitterionic Polysaccharides

Figure 2

(a) Schematic model illustrating the key steps in the presentation pathway of ZPS antigens in DCs. (1) ZPS antigens are internalized by macropinocytosis through PI3-kinase-dependent mechanism and (2) receptor-mediated endocytosis. (3) In early endosomes, DCs potentially undergo an oxidative burst, including the production of nitric oxide (NO) to process the antigen to lower molecular weight (MW) polysaccharides. ZPS-containing early endosomes fuse with late endosomes and then with lysosomes. Macropinosomes fuse with endosomes or lysosomes. (4) The MHCII protein with Ii chain and the DM molecule are assembled in the endoplasmatic reticulum (ER), transported through the Golgi apparatus, and then budded into exocytic vesicles. ZPS-rich endo/lysosomes fuse with exocytic vesicles, creating a MIIC vesicle carrying MHCII, DM, LAMP-1, proteases, and glycosidases. (5) LPS triggers maturation of iDCs with an increased Ii cleavage to CLIP, DM, and MHCII-antigen-binding activity, and protease and glycosidase activity, which possibly process ZPS to fragments of different lower molecular sizes. DM catalyses antigen exchange of CLIP and other self-peptides with ZPS. ZPS is loaded onto MHCII. (6) ZPS/MHCII complexes are shuttled in tubules originating from lysosomes to the cell surface for (7) fusion with the cell membrane and presentation on the cell surface. (8) Presentation of MHCII/ZPS and costimulatory CD40 and CD86 signals induce DC/T cell engagement and immune responses of CD4 T cells in vitro and in vivo through the αβ TCR. (b) ZPS activation of CD8 T cells by just crosslinking the surface TCRs without MHCI-mediated presentation.