Adaptor Protein-3 in Dendritic Cells Facilitates Phagosomal Toll-like Receptor Signaling and Antigen Presentation to CD4+ T Cells

Mantegazza, A. et al. Immunity. 36, 782-794 (2012)

Speaker: Tao-Sheng Liu (劉道生)                               Time: 14:00~15:00, Dec. 26, 2012

Commentator: Dr. Bei-Chang Yang (楊倍昌老師) Place: Room 601

Abstract:

Major histocompatibility complex-II (MHC-II) antigen presentation from phagocytosed peptides needs phagosomal Toll-like receptor signaling. Several factors required for organelle maturation have been identified by studying genetic disorders of organelle biogenesis. For example,Hermansky-Pudlak syndrome (HPS) is a kind of genetic disease in the oculocutaneous albinism family, is an example of defective lysosome-related organelles (LROs). The adaptor protein-3 (AP-3) sorts integral membrane cargoes primarily from the early endosome toward the lysosome. The β3a subunit of AP-3 is genetically inactivated in HPS type 2 patients and its mouse model, the pearl mouse. In plasmacytoid DCs, AP-3 is required to stimulate type I interferon production by carrying activated TLR7 and TLR9 from endosomes to a specialized LRO.¹ This finding raises the possibility that AP-3 might regulate other TLR trafficking in DCs—such as TLR4 delivery from endosomes to maturing phagosomes.² The authors tested whether TLR4-mediated phagosome maturation and antigen presentation in DCs, is altered in pearl mice or not. DCs from pearl mice were impaired in both MHC –II presentation of phagocytosed antigen and proinflammatory TLR signaling from phagosomes. These data show a key role for AP-3 in phagosomal TLR signaling and subsequent delivery of peptide-loaded MHC-II to the plasma membrane. Furthermore, it suggests that recurrent bacterial infections in HPS type 2 patients might in part reflect a defect in TLR-dependent MHC-II presentation by DCs and subsequent proinflammatory responses.

References

1.         Blasius, A.L. et al. Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling inplasmacytoid dendritic cells. Proc. Natl. Acad. Sci. USA 107, 19973–19978.

2.         Husebye, H. et al. The Rab11a GTPase controls Toll-like receptor 4-induced activation of interferon regulatory factor-3 on phagosomes. Immunity 33, 583–596