Slam haplotypes modulate the response to lipopolysaccharide in vivo through control of NKT cell number and function.
CD1d-restricted NKT cells make up an innate-like T cell subset that plays a role in amplifying the response of innate immune leukocytes to TLR ligands. The Slam locus contains genes that have been implicated in innate and adaptive immune responses. In this study, we demonstrate that divergent Slam locus haplotypes modulate the response of macrophages to the TLR4 ligand LPS through their control of NKT cell number and function. In response to LPS challenge in vivo, macrophage TNF production in Slam haplotype-2(+) 129S1/SvImJ and 129X1/SvJ mice was significantly impaired in comparison with macrophage TNF production in Slam haplotype-1(+) 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 alpha-galactosylceramide, and in NKT cell IFN-gamma production after LPS challenge in vivo. Using B6.129c1 congenic mice and adoptive transfer, we found that divergent Slam haplotypes controlled 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 signaling lymphocytic activation molecule 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 cells.
Aktan
Idil
I
Department of Surgery, University of Vermont, College of Medicine, Burlington, VT 05405, USA.
Chant
Alan
A
Borg
Zachary D
ZD
Damby
David E
DE
Leenstra
Paige C
PC
Lilley
Graham W J
GW
Lilley
Graham W G
GW
Petty
Joseph
J
Suratt
Benjamin T
BT
Teuscher
Cory
C
Wakeland
Edward K
EK
Poynter
Matthew E
ME
Boyson
Jonathan E
JE
D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D006239:Haplotypes; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018655:Lymphocyte Count; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics*; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D015703:Antigens, CD; D008070:Lipopolysaccharides; D011956:Receptors, Cell Surface; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1