Natural killer (NK) cells augment atherosclerosis by cytotoxic-dependent mechanisms.
OBJECTIVE
Although natural killer (NK) cells, a key component of the innate immune system, have been identified in human and mouse atherosclerotic lesions, their role in atherosclerosis development remains unclear. To determine their role in atherosclerosis, we used both loss- and gain-of-function experiments in ApoE(-/-) mice fed a high-fat diet.


RESULTS
Treatment of ApoE(-/-) mice with anti-Asialo-GM1 antibodies depleted NK cells without affecting other lymphocytes, including natural killer T cells, and greatly attenuated atherosclerosis. These effects were independent of plasma lipids. To confirm the atherogenicity of NK cells, these cells were isolated from mouse spleens for adoptive transfer into lymphocyte-deficient ApoE(-/-)Rag2(-/-)IL2rg(-/-) mice. Transfer of NK cells from wild-type mice into ApoE(-/-)Rag2(-/-)IL2rg(-/-) mice doubled lesion size, confirming a pro-atherogenic role for NK cells. To determine whether their atherogenicity was dependent on production of interferon-γ (IFN-γ) or cytotoxins, we compared the transfer of NK cells deficient in IFN-γ, perforin, and granzyme B with the transfer of wild-type NK cells. Transfer of IFN-γ-deficient NK cells increased lesion size in the lymphocyte-deficient ApoE(-/-) mice as wild-type NK cells. However, granzyme B- and perforin-deficient NK cells did not affect lesion size. Only wild-type NK cells increased necrotic core size, whereas perforin- and granzyme B-deficient NK cells did not. Plasma lipid levels were largely unaffected by the cell transfer.


CONCLUSIONS
Our loss- and gain-of-function findings provide definitive evidence that NK cells are atherogenic and their production of perforin and granzyme B contributes to atherosclerosis and the expansion of necrotic cores.
Vascular Biology and Atherosclerosis, Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Road Central, Melbourne 8008, Victoria, Australia.
Ahrathy
A
Selathurai
Virginie
V
Deswaerte
Peter
P
Kanellakis
Peter
P
Tipping
Ban-Hock
BH
Toh
Alex
A
Bobik
Tin
T
Kyaw
D019264:Adoptive Transfer; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D053804:Granzymes / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D054353:Perforin / Q000378:metabolism
D001057:Apolipoproteins E; D054353:Perforin; D007371:Interferon-gamma; D053804:Granzymes
ApoE-/- mice; Atherosclerosis; Granzyme B; NK cells; Perforin