CD4+ T cells Regulate Cardiac Ischemia/Reperfusion Injury

Abstract

The mechanisms of healing following myocardial infarction are multifaceted. We tested the hypothesis that chronic, post‐ischemic, cardiac inflammation is regulated by CD4+ T cells through cytokine release and metabolism, and this leads to impaired cardiac function. For these studies, a mouse model of myocardial I/R (30 minutes/24 hours) was employed using wild type (WT) C57Bl/6J mice and CD4+ −/− mice. Based on several hemodynamic measures (EF, SW, dP/dtmax), the cardiac function of CD4+ −/− mice was impaired. Significant induction of monocyte chemotactic protein‐1 (1.9x; MCP‐1) and interferon gamma (3.4x; IFNγ) protein expression occurred following I/R in WT but was absent in CD4+ −/− (n=4; p<0.05). These observations suggested that CD4+ T cells play a pivotal role in the recruitment of innate immune responses following I/R. CD4+ −/− mice had increased cardiac TNFα (3x), ADAM10 (3x), ADAM17 (1.5x), and TLR‐2 (2.3x) mRNA expression relative to WT (n=5; p<0.05). Collectively, these results suggest that CD4+ T cells mediate cardiac dysfunction via TNFα metabolism and inflammatory cascades linked to MCP‐1, IFNγ, and TLR‐2. We propose that CD4+ T cells may bridge the innate immune response to the adaptive immune response in cardiac I/R. This may provide novel mechanistic strategies to target CD4+ T cells and treat chronic reperfusion injury syndromes. Supported by HL077566, HL085119, AHA SDG and AHA 10POST3870022.