Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 5, Pages 1596-1601Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0409015102
Keywords
cytokines; T cells; antibodies
Categories
Funding
- NHLBI NIH HHS [HL56989, HL69464, R01 HL069464, P50 HL56985, P50 HL056989, P50 HL056985] Funding Source: Medline
- NIAID NIH HHS [R01 AI048126, AI48126] Funding Source: Medline
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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-cleficient 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.
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