Presentation to CD4+ T cells of antigen bound to major histocompatibility complex II (MHC II) molecules on the surface of antigen-presenting cells (APCs) is critical for an effective adaptive immune response. MHC II molecules are also implicated in “reverse” signaling in APCs, modulating responses such as adhesion and cytokine production (see commentary by Hassan and Mourad). Liu et al. found that MHC II–deficient (H2–/–) mice produced lower amounts of proinflammatory cytokines in response to Toll-like receptor (TLR) ligands than did similarly treated wild-type (WT) mice, which was associated with increased survival of H2–/– mice challenged with the toxin lipopolysaccharide (LPS) or with live bacteria. APCs from H2–/– mice produced less proinflammatory cytokines and type I interferon in response to TLR ligands than did WT mice. MHC II deficiency in APCs resulted in impaired activation of mitogen-activated protein kinases downstream of TLRs and their adaptor proteins MyD88 and TRIF. A screen of the activation status of tyrosine kinases in TLR-stimulated WT and H2–/– APCs revealed that MHC II was required for the full activation of Bruton’s tyrosine kinase (Btk). TLR-dependent responses were impaired in Btk–/– mice compared with those of WT mice, and constitutively active Btk restored the production of proinflammatory cytokines in H2–/– mice. MHC II physically associated with Btk (and the costimulatory molecule CD40) in TLR-stimulated APCs, but only in endosomes and not at the plasma membrane. Finally, MHC II was required for the TLR-stimulated interaction between Btk and TLR adaptor proteins in endosomes. Together, these data suggest that MHC II is required for full activation of TLRs in APCs, indicating a role for MHC II in mediating effective innate immune responses.
X. Liu, Z. Zhan, D. Li, L. Xu, F. Ma, P. Zhang, H. Yao, X. Cao, Intracellular MHC class II molecules promote TLR-triggered innate immune responses by maintaining activation of the kinase Btk. Nat. Immunol. 12, 416–424 (2011). [PubMed]
G. S. Hassan, W. Mourad, An unexpected role for MHC class II. Nat. Immunol. 12, 375–376 (2011). [PubMed]