Immunobiological understanding of RP105 was shaped by its discovery and initial analysis in B cells. Ab-mediated cross-linking of RP105 leads to B cell activation and proliferation, providing protection against radiation- and steroid-induced apoptosis (1
), but sensitization to apoptosis in response to BCR ligation (2
). Anti-RP105-driven proliferative responses have been studied in detail; roles for the Lyn/CD19/Vav1 complex, Bruton's tyrosine kinase, protein kinase CβI/II and MEK have been found (1
Cloning revealed RP105 to be a TLR homolog, albeit one lacking a signaling TIR domain. Further, while LPS-driven TLR4 signaling depends on the association of TLR4 with MD-2, RP105 activity depends on its association with the MD-2 homolog, MD-1. Subsequent study revealed an apparent role for RP105 in TLR4 signaling in B cells. Whereas LPS-induced B cell proliferation is strictly dependent on TLR4, B cells from RP105−/−
mice exhibit impaired LPS-driven proliferation in the face of normal proliferative responses to engagement of TLR9, IgM or CD40 (6
). Such data suggested that RP105 facilitates TLR4 signaling in B cells, although the underlying mechanisms have not been identified. The converse is not the case, however; B cell proliferation induced by Ab to RP105 is unimpaired in mice lacking TLR4 (4
Further analysis revealed a broader pattern of expression. In addition to B cells, RP105 is expressed by diverse cell types expressing TLRs, including most APCs (8
). Notably, RP105 was shown to inhibit TLR4 signaling in HEK293 cells, inhibit TLR4 signaling in dendritic cells, and restrain in vivo
cytokine production in response to LPS (8
). Recent solution of the crystal structure of RP105/MD-1 has been informative (9
). The overall architecture of the 1:1 RP105/MD-1 complex is similar to that of TLR4/MD-2. However, RP105/MD-1 assembles into a unique 2:2 homodimer, with head-to-head dimerization of RP105's C-terminal leucine-rich repeats. This displaces the intracellular domains of RP105 to opposing sides of the complex; unlike the tail-to-tail dimerization of the N-terminal leucine-rich repeats observed in liganded TLR dimers which juxtaposes intracellular TIR domains, allowing signaling. Modeling of the interaction of RP105/MD-1 with TLR4/MD-2 based on their solved structures suggests that the TIR domains of TLR4 are prevented from apposition by the interaction of TLR4/MD-2 with RP105/MD-1 (9
). Such modeling fails to suggest a mechanism by which RP105/MD-1 might facilitate TLR4 signaling in B cells.
In light of these paradoxical findings—with RP105 appearing to facilitate or inhibit TLR4 signaling depending on the cell type involved—we reinvestigated the B cell proliferative responses of RP105−/− mice.