Deficiency of invariant V alpha 14 natural killer T cells decreases atherosclerosis in LDL receptor null mice.
OBJECTIVE
CD1d-restricted natural killer T (NKT) cells function by regulating numerous immune responses during innate and adaptive immunity. Depletion of all populations of CD1d-dependent NKT cells has been shown by several groups to reduce atherosclerosis in two different mouse models of the disease. In this study, we determined if removal of a single (V alpha 14) NKT cell population protects mice from the disease.


RESULTS
Targeted deletion of the J alpha 18 gene results in selective depletion of CD1d-dependent V alpha 14 NKT cells in C57BL/6 mice without affecting the population of other NKT, NK, and conventional T cells. Therefore, to study the effect of V alpha 14 NKT cell depletion on the progression of atherosclerosis, we examined the extent of lesion formation using paired littermate LDL receptor null mice that were either +/+ or -/- for the J alpha 18 gene following the feeding of these mice a cholesterol- and fat-enriched diet for 8 weeks. At the end of the study, we found no difference in either serum total- or lipoprotein-cholesterol distributions between groups. However, quantification of atherosclerosis revealed that V alpha 14 NKT cell deficiency significantly decreased lesion size in the aortic root (20-28%) and arch (28-38%) in both genders of mice. By coupling the techniques of laser capture microdissection with quantitative real-time RT-PCR, we found that expression of the proatherogenic cytokine interferon (IFN)-gamma was significantly reduced in lesions from J alpha 18-/- mice.


CONCLUSIONS
This study is the first to identify a specific subpopulation of NKT cells that promotes atherosclerosis via a mechanism appearing to involve IFN-gamma expression.
Rogers
Leah
L
Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Canada.
Burchat
Sarah
S
Gage
Jessica
J
Hasu
Mirela
M
Thabet
Mohamad
M
Willcox
Lindsay
L
Wilcox
Lindsay
L
Ramsamy
Tanya A
TA
Whitman
Stewart C
SC
D000818:Animals; D018949:Antigens, CD1 / Q000378:metabolism*; D055610:Antigens, CD1d; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017252:CD3 Complex / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D042282:Microdissection / Q000379:methods; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*
D018949:Antigens, CD1; D055610:Antigens, CD1d; D017252:CD3 Complex; D000949:Histocompatibility Antigens Class II; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011973:Receptors, LDL; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D002784:Cholesterol