T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses.
The influence of the immune system on atherosclerosis involves both helper T (Th) cell and antibody responses to plaque antigens. These responses may have proatherogenic and protective effects. T-bet is a transcription factor required for Th1 differentiation and regulates the balance between Th1 and Th2 responses in inflammatory diseases. To clarify how helper T cell subset differentiation influences atherosclerosis, we compared lesion development and immune responses to plaque antigens in low-density lipoprotein receptor-deficient (Ldlr-/-) mice with or without functional T-bet genes. Atherosclerosis was significantly reduced in T-bet-deficient Ldlr-/- mice compared with Ldlr-/- controls, and the lesions that did develop in the absence of T-bet had less smooth muscle cell content. Furthermore, T-bet deficiency caused a Th2 switch in the response to the atherosclerosis-associated antigen heat shock protein-60, and a change in T-dependent isotypes of oxidized LDL-specific antibodies. Of particular significance, T-bet deficiency caused a >250% increase in the titer of E06 antibodies, which are known to be atheroprotective and whose production by B-1 B cells is enhanced by IL-5. These findings establish that T cell subset differentiation influences both T cell and antibody responses that modulate atherosclerosis, and validate the therapeutic goal of skewing T responses to atherosclerosis-associated antigens.
Buono
Chiara
C
Vascular Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Binder
Christoph J
CJ
Stavrakis
George
G
Witztum
Joseph L
JL
Glimcher
Laurie H
LH
Lichtman
Andrew H
AH
D000818:Animals; D001161:Arteriosclerosis / Q000097:blood / Q000276:immunology* / Q000517:prevention & control; D015704:CD4 Antigens / Q000276:immunology; D002784:Cholesterol / Q000097:blood; D007136:Immunoglobulins / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics*; D020825:T-Box Domain Proteins; D016176:T-Lymphocyte Subsets / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics*; D000098815:T-bet Transcription Factor
D015704:CD4 Antigens; D007136:Immunoglobulins; D011973:Receptors, LDL; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D002784:Cholesterol