Intracellular MHC class II molecules promote TLR-triggered innate immune responses by maintaining activation of the kinase Btk

Liu, X. et al., Nature Immunology 12, 416-424 (2011)

Speaker: Yu-Pu Hsia (夏雨璞)                                      Time: 14:00~15:00, Nov. 16, 2011

Commentator: Dr. Pei-Jane Tsai (蔡佩珍老師)            Place: Room 601

Abstract:

The innate immune system provides the first line of defense against invading microorganisms. Toll-like receptors (TLRs) recognizes pathogen-associated molecular patterns, after activation of the TLRs, related immune responses are produced [1]. Major histocompatibility complex (MHC) class II presenting peptides to CD4⁺T cells processes positive and negative selection. Pathogens down-regulate the expression of MHC class II to avoid immune attack [2]. Previous study shows that crosstalk between MHC molecules and TLRs is important in the immune response, but the mechanism remains unclear [3]. In this study, the authors demonstrated that the mice loss of MHC class II (H2^-/-) produced less proinflammatory cytokines and type I interferons after challenged with TLR ligands. Reconstitution of bone marrow cells from H2^+/+ or H2^-/- mice into lethally irradiated wild-type mice demonstrated defense to endotoxic shock in H2^-/- mice. Lack of MHC class II on APCs cause impaired TLR-triggered inflammatory response by MyD88-dependent and TRIF-dependent pathways. Btk is a cytoplasmic tyrosine kinase which is important in B-lymphocyte development, differentiation, and signaling that involved in TLR pathway. Following TLRs stimulation of H2^-/- peritoneal macrophages Btk phosphorylation is reduced. Importantly, overexpression of MHC class II recovered Btk activation in H2^-/- peritoneal macrophages. These data suggest that MHC class II molecules facilitate TLR-triggered inflammatory response via phosphorylation of Btk. The authors also found that costimulatory protein CD40 was essential when MHC class II actived Btk, and the mechanism was presented at intracellular but not plasma membrane. Then Btk could interact with MyD88 and TRIF to enhance TLR signaling. In conclusion, intracellular MHC class II acts as adaptor to from a complex with Btk and CD40 and further promotes the TLR response.

References:

1.          McGettrick AF et al. 2010. Localisation and trafficking of Toll-like receptors: an important mode of regulation. Curr Opin Immunol. 22,20-27.

2.          Lapaque N et al. 2009. Salmonella regulates polyubiquitination and surface expression of MHC class II antigens. Proc Natl Acad Sci U S A 106,14052-14057

3.          Kissner TL et al. 2011. Activation of MyD88 Signaling upon Staphylococcal Enterotoxin Binding to MHC Class II Molecules. PLoS One. 6, e15985.