Impaired regulatory T-cell response and enhanced atherosclerosis in the absence of inducible costimulatory molecule.
BACKGROUND
T-cell-mediated immunity contributes to the pathogenesis of atherosclerosis, but little is known about how these responses are regulated. We explored the influence of the inducible costimulatory molecule (ICOS) on atherosclerosis and associated immune responses.


RESULTS
Bone marrow chimeras were generated by transplanting ICOS-deficient or wild-type bone marrow into irradiated atherosclerosis-prone, LDR receptor-deficient mice, and the chimeric mice were fed a high-cholesterol diet for 8 weeks. Compared with controls, mice transplanted with ICOS-deficient marrow had a 43% increase in the atherosclerotic burden, and importantly, their lesions had a 3-fold increase in CD4+ T cells, as well as increased macrophage, smooth muscle cell, and collagen content. CD4+ T cells from ICOS-deficient chimeras proliferated more and secreted more interferon-gamma and tumor necrosis factor-alpha than T cells from control mice, which suggests a lack of regulation. FoxP3+ regulatory T cells (Treg) were found to constitutively express high ICOS levels, which suggests a role for ICOS in Treg function. ICOS-deficient mice had decreased numbers of FoxP3+ Treg and impaired in vitro Treg suppressive function compared with control mice.


CONCLUSIONS
ICOS has a key role in regulation of atherosclerosis, through its effect on regulatory T-cell responses.
Gotsman
Israel
I
Immunology Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, Mass 02115, USA.
Grabie
Nir
N
Gupta
Rajat
R
Dacosta
Rosa
R
MacConmara
Malcolm
M
Lederer
James
J
Sukhova
Galina
G
Witztum
Joseph L
JL
Sharpe
Arlene H
AH
Lichtman
Andrew H
AH
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D060889:Inducible T-Cell Co-Stimulator Protein; D008212:Lymphocyte Depletion / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology
D000945:Antigens, Differentiation, T-Lymphocyte; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein