Abstract
Both conventional and regulatory CD4+ T-cells rely on costimulatory signals mediated by cell surface receptors including CD28 for full activation. We showed previously that stimulation of CD4+ Foxp3+ regulatory T-cells by superagonistic anti-CD28 monoclonal antibodies (mAb) improves myocardial healing after experimental myocardial infarction (MI). However, the effect of ligand binding blocking anti-CD28 monoclonal antibodies has not yet been tested in this context. We hypothesize that ligand blocking anti-CD28 mAb treatment might favorably impact on healing after MI by limiting the activation of conventional CD4+ T-cells. Therefore, we studied the therapeutic effect of the recently characterized mAb E18 which blocks ligand binding to CD28 in a mouse permanent coronary ligation model. E18 or an irrelevant control mAb was applied once on day two after myocardial infarction to wildtype mice. Echocardiography was performed on day 7 after MI. E18 treatment improved the survival and reduced the incidence of left ventricular ruptures after experimental myocardial infarction. Accordingly, although we found no difference in infarct size, there was significantly less left ventricular dilation after E18 treatment in surviving animals as determined by echocardiography at day 7 after MI. In sham operated control mice neither antibody had an impact on body weight, survival, and echocardiographic parameters. Mechanistically, compared to control immunoglobulin, E18 treatment reduced the number of CD4+ T-cells and monocytes/macrophages within the infarct and periinfarct zone on day 5. This was accompanied by an upregulation of arginase which is a marker for alternatively differentiated macrophages. The data indicate that CD28-dependent costimulation of CD4+ T-cells impairs myocardial healing and anti-CD28 antibody treatment constitutes a potentially clinically translatable approach to improve the outcome early after MI.
Highlights
Foxp3+ regulatory T-cells (Tregs) infiltrating the infarcted myocardium have been shown to favorably regulate macrophage differentiation, monocyte recruitment, extracellular matrix de novo formation, and angiogenesis [1,2,3]
Animals were randomly allocated to treatment with a single dose of the ligand binding inhibiting anti-CD28 monoclonal antibodies (mAb) E18 or a mAb of the same isotpye (IgG2b), but irrelevant specificity, on day two after myocardial infarction (MI)
We found that application of the ligand blocking anti-CD28 mAb E18 reduced the numbers of CD4+ T-cells within the infarcted myocardium while the proportion of conventional and regulatory T-cells was unchanged in both, the infarcted myocardium and in the draining lymph nodes
Summary
Foxp3+ regulatory T-cells (Tregs) infiltrating the infarcted myocardium have been shown to favorably regulate macrophage differentiation, monocyte recruitment, extracellular matrix de novo formation, and angiogenesis [1,2,3]. These processes play central roles in myocardial healing after myocardial infarction (MI). As the costimulatory molecule CD28 is a key modulator of T-cell activation, it constitutes an attractive therapeutic target in T-cell dependent diseases [6] To this end, monoclonal antibodies have been developed which either block ligand binding or superagonistically stimulate CD28 (reviewed in [6]). Upon superagonistic monoclonal anti-CD28 injection Tregs are preferentially activated over Tconvs and expanded leading to potent inhibition of (pathogenic) Tconv cell responses [12,13,14,15,16,17]
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