Siglec-G Negatively Regulates Antigen Cross-presentation Of Dendritic Cells And The Underlying Mechanisms

MHC class Ⅰ and MHC class Ⅱ-associated antigen presentation is generally governed by two separate pathways. Classical antigen-presentation studies showed that MHC class Ⅰ molecules present peptides derived from proteins synthesized within the cell, whereas MHC class Ⅱ molecules present exogenous proteins captured from the environment. In some cases, however, antigen-presenting cells (APCs) can endocytose exogenous antigens and cross-present them to naive CD8+T lymphocytes by MHC class Ⅰ pathway, this process is called "cross presentation". As the most efficient professional antigen presenting cells, DCs are the main cell type which may present extracellular antigens to naive CD8+T lymphocytes in vivo. Several recent studies showed DCs have adapted their endocytic and phagocytic pathways to the cross presentation function. These specializations of the DC include the regulated transport of MHC molecules, the transport of antigen from endosomes and phagosomes into the cytosol, and the recruitment of ER proteins to phagosomes. However, the molecular mechanisms that make DCs such unique antigen cross presenting cells with cross presentation function are still not clear enough.Here we report that Siglec-G deficiency protect mice from infection with Listeria monocytogenes, an intracellular bacterium, which needs effective cytotoxic T cells for complete clearance from the host. Siglec-G could suppress the activation and proliferation of CD8+ CTL by inhibit the cross presentation of DC but does not affect the antigen presentation via MHC-II pathway. The expression of MHC Ⅰ-exogenous antigen peptide complex on DC is down regulated by Siglec-G. Siglec-G could recruit Shpl to the phagosomes in DCs, dephosphorylating p47phox to down regulate the assembly of NOX2. The suppressed recruitment of NOX2 to phagosomes mediates less production of ROS, which results in less proton consumption in the phagosome lumen, and leads phagosome acidification. Without Siglec-G, the DCs phagosomal pH could be less acidification and protect the exogenous antigen from excessive hydrolysis, leads an effective cross presentation of DCs. Therefore, Siglec-G plays a critical role in negatively regulates DCs to cross present antigen in the initiation of antigen-specific CD8+T cell response.