Response to Microbial Membranes Links TLR2 and TLR4/MD-2 in Antibody The Radioprotective 105/MD-1 Complex

Low-affinity IgG3 Abs to microbial membranes are important for primary immune defense against microbes, but little is known about the importance of TLRs in their production. IgG3 levels were extremely low in mice lacking radioprotective 105 (RP105), a B cell surface molecule structurally related to TLRs. RP105 ؊/؊ B cells proliferated poorly in response to not only the TLR4 ligand LPS but also TLR2 ligand lipoproteins, both of which mediate the immunostimulatory activity of microbial membranes. I nnate immunity provides a first line of defense against microbial pathogens (1) and is dependent on a restricted set of nonvariant, germline-encoded molecules that include secreted opsonins, C-type lectins, and scavenger receptors (2). B cells can contribute to innate immunity by secreting Abs with similarities to innate immune receptors in that they are semi-invariant and reactive with both self and microbial membrane glycolipids (3). These are principally IgM and IgG3 Abs that directly bind to microbial membranes, activate complement, facilitate their phago-cytosis, and enhance their immunogenicity through Ag-trapping in secondary lymphoid organs (4, 5). They are produced as natural Abs to self-antigens and microbial flora or produced in primary, T-independent (TI) 5 responses during microbial infections. B1 cells and splenic marginal zone (MZ) B cells are important for producing these protective IgM and IgG3 Abs. However, the recognition molecules on B cells that mediate these TI Ab responses have been poorly understood. Microbial membranes were known to stimulate immune cells. LPS and lipoproteins were identified as principal components of the immunostimulating activity of microbial membranes. These components have turned out to be ligands for TLRs, a family of innate immune receptors for microbial products (6, 7). Het-erodimers such as TLR1/TLR2 or TLR2/TLR6 mediate responses to particular membrane lipoproteins (8), whereas the TLR4/MD-2 complex is essential for LPS recognition (9, 10). LPS is a proto-typical TI type 1 Ag. That is, it elicits Ab production without T cell help. Since B cells lacking TLR4 or MD-2 do not respond to LPS (10, 11), TLR4/MD-2 is required for LPS-induced Ab production. Much less is known about the importance of TLR2-mediated Ab responses to microbial lipoproteins. B cells express another pair of TLR family proteins that are also important for LPS responses. Radioprotective 105 (RP105) forms a complex with MD-1 and can transmit powerful survival as well as proliferation signals when cross-linked by Abs (12–14). RP105 Ϫ/Ϫ or MD-1 Ϫ/Ϫ mice, like animals deficient in TLR4 …