Expansion of CD25+ Innate Lymphoid Cells Reduces Atherosclerosis.
OBJECTIVE
Innate lymphoid cells (ILCs) are a newly discovered subset of immune cells that promote tissue homeostasis and protect against pathogens. ILCs produce cytokines also produced by T lymphocytes that have been shown to affect atherosclerosis, but the influence of ILCs on atherosclerosis has not been explored.


RESULTS
We demonstrate that CD25(+) ILCs that produce type 2 cytokines (ILC2s) are present in the aorta of atherosclerotic immunodeficient ldlr(-/-)rag1(-/-) mice. To investigate the role of ILCs in atherosclerosis, ldlr(-/-)rag1(-/-) mice were concurrently fed an atherogenic diet and treated with either ILC-depleting anti-CD90.2 antibodies or IL-2/anti-IL-2 complexes that expand CD25(+) ILCs. Lesion development was not affected by anti-CD90.2 treatment, but was reduced in IL-2/anti-IL-2-treated mice. These IL-2-treated mice had reduced very low-density lipoprotein cholesterol and increased triglycerides compared with controls and reduced apolipoprotein B100 gene expression in the liver. IL-2/anti-IL-2 treatment caused expansion of ILC2s in aorta and other tissues, elevated levels of IL-5, systemic eosinophila, and hepatic eosinophilic inflammation. Blockade of IL-5 reversed the IL-2 complex-induced eosinophilia but did not change lesion size.


CONCLUSIONS
This study demonstrates that expansion of CD25-expressing ILCs by IL-2/anti-IL-2 complexes leads to a reduction in very low-density lipoprotein cholesterol and atherosclerosis. Global depletion of ILCs by anti-CD90.2 did not significantly affect lesion size indicating that different ILC subsets may have divergent effects on atherosclerosis.
From the Departments of Pathology (D.E., A.C.F., N.A.-G., F.K., T.C., P.J., N.G., A.H.L.) and Surgery (J.A.L.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Daniel
D
Engelbertsen
From the Departments of Pathology (D.E., A.C.F., N.A.-G., F.K., T.C., P.J., N.G., A.H.L.) and Surgery (J.A.L.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Amanda C
AC
Foks
From the Departments of Pathology (D.E., A.C.F., N.A.-G., F.K., T.C., P.J., N.G., A.H.L.) and Surgery (J.A.L.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Noah
N
Alberts-Grill
From the Departments of Pathology (D.E., A.C.F., N.A.-G., F.K., T.C., P.J., N.G., A.H.L.) and Surgery (J.A.L.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Felicia
F
Kuperwaser
From the Departments of Pathology (D.E., A.C.F., N.A.-G., F.K., T.C., P.J., N.G., A.H.L.) and Surgery (J.A.L.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Tao
T
Chen
From the Departments of Pathology (D.E., A.C.F., N.A.-G., F.K., T.C., P.J., N.G., A.H.L.) and Surgery (J.A.L.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
James A
JA
Lederer
From the Departments of Pathology (D.E., A.C.F., N.A.-G., F.K., T.C., P.J., N.G., A.H.L.) and Surgery (J.A.L.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Petr
P
Jarolim
From the Departments of Pathology (D.E., A.C.F., N.A.-G., F.K., T.C., P.J., N.G., A.H.L.) and Surgery (J.A.L.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Nir
N
Grabie
From the Departments of Pathology (D.E., A.C.F., N.A.-G., F.K., T.C., P.J., N.G., A.H.L.) and Surgery (J.A.L.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA. alichtman@partners.org.
Andrew H
AH
Lichtman
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000097:blood; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015415:Biomarkers / Q000097:blood; D049109:Cell Proliferation / Q000187:drug effects*; D015243:Cholesterol, VLDL / Q000097:blood; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects*; D007376:Interleukin-2 / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism*; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D014280:Triglycerides / Q000097:blood
D000906:Antibodies; C415826:Apob protein, mouse; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D015415:Biomarkers; D015243:Cholesterol, VLDL; D018398:Homeodomain Proteins; C508018:Il2ra protein, mouse; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D015848:Interleukin-5; D011973:Receptors, LDL; D014280:Triglycerides; C064658:RAG-1 protein
atherosclerosis; cytokines; eosinophils; interleukin; triglycerides