Slam haplotypes modulate the response to LPS in vivo through control of NKT cell number and function1

• Published in: The Journal of immunology (1950) Vol. 185; no. 1; pp. 144 - 156
• Main Authors: Aktan, Idil, Chant, Alan, Borg, Zachary D., Damby, David E., Leenstra, Paige, Lilley, Graham, Petty, Joseph, Suratt, Benjamin T., Teuscher, Cory, Wakeland, Edward K., Poynter, Matthew E., Boyson, Jonathan E.
• Format: Journal Article
• Language: English
• Published: 07.06.2010
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0902658

CD1d-restricted NKT cells comprise an innate-like T cell subset that hasbeen demonstrated to play a role in amplifying the response of innate immune leukocytesto TLR ligands. The Slam locus contains genes that have been implicated in both innate and adaptive immune responses. Here, we demonstrate that divergent Slam locus haplotypesmodulate the response of macrophages to TLR ligands such as LPS through their control of NKT cell number and function. In response to LPS challenge in vivo , macrophage TNF production in Slam haplotype-2-associated 129S1/SvImJ and 129X1/SvJ mice was significantly impaired in comparison to macrophage TNF production in Slam haplotype -1-positive C57BL/6J mice. Although no cell-intrinsic differences in macrophage responses to LPS were observed between strains, 129 mice were found to be deficient in liver NKT cell number, in NKT cell cytokine production in response to the CD1d ligand α-galactosylceramide, and in NKT cell IFN-γ production after LPS challenge in vivo . Using B6.129 c1congenic mice and adoptive transfer, we found that divergent Slam haplotypes controlled both the response to LPS in vivo as well as the diminished NKT cell number and function, and that these phenotypes were associated with differential expression of SLAM family receptors on NKT cells. These data suggest that the polymorphisms that distinguish two Slam haplotypes significantly modulate the innate immune response in vivo through their effect on NKT cell s.