Induction of a regulatory T cell type 1 response reduces the development of atherosclerosis in apolipoprotein E-knockout mice.
BACKGROUND
T helper type 1 (Th1) response plays a permissive role in atherosclerosis. We hypothesized that adoptive transfer of a novel subtype of T lymphocytes called regulatory T cells type 1 (Tr1) would inhibit Th1 responses by inducing a bystander immune suppression and therefore limit the development of atherosclerosis.


RESULTS
Clones of ovalbumin (OVA)-specific Tr1 cells expanded in vitro were administered intraperitoneally (106 cells per mouse) with their cognate antigen (50 microg of OVA subcutaneously in complete Freund's adjuvant [CFA]) to female apolipoprotein E-knockout mice. A group of mice received only (OVA/CFA) immunization without Tr1 cells. Two other control groups received no immunization and were injected with either Tr1 cells or saline. After 9 weeks of treatment, mice injected with (OVA/CFA)+OVA-specific Tr1 cells showed a significant decrease in Th1 responses, as revealed by a decrease in OVA-specific IgG2a serum levels (P<0.0001), a decrease in the production of interferon-gamma (P<0.001), and an increase in interleukin-10 production (P<0.001) by cultured spleen and lymph T cells compared with controls. In addition, cytokine production by concanavalin A-stimulated spleen cells showed a clear switch to a regulatory immune response in mice treated with (OVA/CFA)+Tr1. This was associated with a significant reduction in atherosclerotic lesion size in both the thoracic aorta and aortic sinus of mice treated with (OVA/CFA)+Tr1 compared with controls (P=0.002 to P<0.0001). Plaques of mice injected with (OVA/CFA)+Tr1 showed significantly lower accumulation of macrophages and T cells than plaques of control mice.


CONCLUSIONS
Tr1-type regulatory immune response reduces the development of experimental atherosclerosis.
Mallat
Ziad
Z
Institut National de la Santé et de la Recherche Médicale, INSERM U541, Institut Fédératif de Recherche Circulation Paris VII, Hôpital Lariboisière, Paris, France. mallat@larib.inserm.fr
Gojova
Andrea
A
Brun
Valérie
V
Esposito
Bruno
B
Fournier
Nathalie
N
Cottrez
Françoise
F
Tedgui
Alain
A
Groux
Hervé
H
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D024201:Bystander Effect / Q000276:immunology; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D002999:Clone Cells; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005620:Freund's Adjuvant / Q000276:immunology; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007165:Immunosuppression Therapy / Q000379:methods; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology* / Q000637:transplantation; D018417:Th1 Cells / Q000276:immunology / Q000502:physiology
D001057:Apolipoproteins E; D016207:Cytokines; D007074:Immunoglobulin G; D016753:Interleukin-10; D007073:Immunoglobulin E; D007371:Interferon-gamma; D010047:Ovalbumin; D005620:Freund's Adjuvant; D002784:Cholesterol