Abstract 212: Cd4+ T-cell Activation By T-cell Receptor Engagement Contributes To Myocardial Ischemia-reperfusion Injury
Background: We have recently shown that CD4+ but not CD8+ T-cells contribute to ischemia-reperfusion injury of the myocardium. We therefore hypothesized that CD4+ T-cells become activated by autoantigen recognition via their T-cell receptor during reperfusion.
Methods and Results: Infarct size as percent of the area-at-risk was determined by combined Evans` blue and triphenyltetrazolium (TTC) staining after 30 minutes of in vivo ischemia followed by 24 hours reperfusion in mice. After 24 hours of reperfusion there was a significantly increased population of CD4+ T-cells which expressed the surface protein CD40L in comparison to sham operated mice [n≥7; p<0.05; WT 10.8 ± 0.2% vs. sham 6.4 ± 0.5%]. CD40L is typically expressed in T-cells activated by T-cell receptor engagement. OT-II mice carry a transgenic T-cell receptor with specificity for an ovalbumin-derived peptide. These mice have a limited T-cell receptor repertoire, dominated by specificity for the irrelevant antigen ovalbumin. After 30 minutes of ischemia and 24 hours of reperfusion OT-II mice showed significantly reduction in infarct size [n≥4; p= 0.02; infarct/area at risk: OTII mice 38.9 ± 2.4% vs. WT mice 63.7 ± 6.6 % ]. Administration of a CD40L blocking antibody to wildtype mice also reduced infarct size when compared to administration of isotype-matched antibodies [n≥6; p = 0.03; infarct/ area at risk: anti-CD154 treatment 60.4 ± 3.4% vs. control 75.3 ± 4.1%]. CD4+ CD25+ Foxp3+ T-cells (natural T-regulatory cells) have a low activation threshold and constitute a T-cell subset with reactivity against autoantigens. Depletion of these cells by diphtheria-toxin application in a mouse model expressing the diphtheria-toxin receptor under the Foxp3 promotor also resulted in a significant reduction of infarct size when compared to diphtheria-toxin treated wildtype mice [n≥4; p=0.03; infarct/ area at risk: Treg-depleted DEREG mice 51.9± 3% vs. WT littermates 72.3± 2%].
Conclusion: Our results indicate that CD4+ T-cells that have been activated by an MHC class II/ T-cell receptor dependent mechanism, presumably by autoantigen recognition, contribute to myocardial ischemia-reperfusion injury.
- © 2013 by American Heart Association, Inc.