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

Nat Immunol. 2011 May;12(5):416-24. doi: 10.1038/ni.2015. Epub 2011 Mar 27.


The molecular mechanisms involved in the full activation of innate immunity achieved through Toll-like receptors (TLRs) remain to be fully elucidated. In addition to their classical antigen-presenting function, major histocompatibility complex (MHC) class II molecules might mediate reverse signaling. Here we report that deficiency in MHC class II attenuated the TLR-triggered production of proinflammatory cytokines and type I interferon in macrophages and dendritic cells, which protected mice from endotoxin shock. Intracellular MHC class II molecules interacted with the tyrosine kinase Btk via the costimulatory molecule CD40 and maintained Btk activation, but cell surface MHC class II molecules did not. Then, Btk interacted with the adaptor molecules MyD88 and TRIF and thereby promoted TLR signaling. Therefore, intracellular MHC class II molecules can act as adaptors, promoting full activation of TLR-triggered innate immune responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / immunology
  • Agammaglobulinaemia Tyrosine Kinase
  • Animals
  • Antigen-Presenting Cells / enzymology
  • Antigen-Presenting Cells / immunology
  • CD40 Antigens / immunology
  • Cell Line
  • Cytokines / blood
  • Cytokines / immunology
  • Enzyme Activation
  • Histocompatibility Antigens Class II / immunology*
  • Immunity, Innate / immunology*
  • Immunoblotting
  • Interferon-gamma / blood
  • Interferon-gamma / immunology
  • Kaplan-Meier Estimate
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / immunology
  • Protein-Tyrosine Kinases / immunology
  • Protein-Tyrosine Kinases / metabolism*
  • Sepsis / immunology
  • Specific Pathogen-Free Organisms
  • Toll-Like Receptors / immunology*


  • Adaptor Proteins, Vesicular Transport
  • CD40 Antigens
  • Cytokines
  • Histocompatibility Antigens Class II
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • TICAM-1 protein, mouse
  • Toll-Like Receptors
  • Interferon-gamma
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase