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MHC Class II Molecules Control Murine B Cell Responsiveness to Lipopolysaccharide Stimulation¹

Instituto Gulbenkian de Ciência, Oeiras, Portugal

LPS is a strong stimulator of the innate immune system and inducer of B lymphocyte activation. Two TLRs, TLR4 and RP105 (CD180), have been identified as mediators of LPS signaling in murine B cells, but little is known about genetic factors that are able to control LPS-induced cell activation. We performed a mouse genome-wide screen that aside from identifying a controlling locus mapping in the TLR4 region (logarithm of odds score, 2.77), also revealed that a locus closely linked to the MHC region (logarithm of odds score, 3.4) governed B cell responsiveness to LPS stimulation. Using purified B cells obtained from MHC congenic strains, we demonstrated that the MHC^b haplotype is accountable for higher cell activation, cell proliferation, and IgM secretion, after LPS stimulation, when compared with the MHC^d haplotype. Furthermore, B cells from MHC class II^–/– mice displayed enhanced activation and proliferation in response to LPS. In addition, we showed that the MHC haplotype partially controls expression of RP105 (a LPS receptor molecule), following a pattern that resembles the LPS responsiveness phenotype. Together, our results strongly suggest that murine MHC class II molecules play a role in constraining the B cell response to LPS and that genetic variation at the MHC locus is an important component in controlling B cell responsiveness to LPS stimulation. This work raises the possibility that constraining of B cell responsiveness by MHC class II molecules may represent a functional interaction between adaptive and innate immune systems.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Fundação para a Ciência e Tecnologia Grant SAU-MMO/60964/2004.

² Address correspondence and reprint requests to Carlos Penha-Gonçalves, Instituto Gulbenkian de Ciência, Apartado 14 P-2781-901, Oeiras, Portugal. E-mail address: cpenha{at}igc.gulbenkian.pt

³ Abbreviations used in this paper: LOD, logarithm of odds; Tg, transgenic; QTL, quantitative trait loci.