Myocardial infarction triggers cardioprotective antigen-specific T helper cell responses
Max Rieckmann, … , Ulrich Hofmann, Gustavo Campos Ramos
Max Rieckmann, … , Ulrich Hofmann, Gustavo Campos Ramos
Published August 13, 2019
Citation Information: J Clin Invest. 2019;129(11):4922-4936. https://doi.org/10.1172/JCI123859.
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Research Article Cardiology Immunology Article has an altmetric score of 53

Myocardial infarction triggers cardioprotective antigen-specific T helper cell responses

Abstract

T cell autoreactivity is a hallmark of autoimmune diseases but can also benefit self-maintenance and foster tissue repair. Here, we investigated whether heart-specific T cells exert salutary or detrimental effects in the context of myocardial infarction (MI), the leading cause of death worldwide. After screening more than 150 class II–restricted epitopes, we found that myosin heavy chain α (MYHCA) was a dominant cardiac antigen triggering post-MI CD4+ T cell activation in Balb/c mice. Transferred MYHCA614–629-specific CD4+ T cells (TCR-M cells) selectively accumulated in the myocardium and mediastinal lymph nodes (med-LNs) of infarcted mice, acquired a Treg phenotype with a distinct prohealing gene expression profile, and mediated cardioprotection. Myocardial Tregs were also detected in autopsy samples from patients who had had a MI. Noninvasive PET/CT imaging using a CXCR4 radioligand revealed enlarged med-LNs with increased cellularity in patients with MI. Notably, the med-LN alterations observed in MI patients correlated with the infarct size and cardiac function. Taken together, the results obtained in our study provide evidence that MI context induces prohealing T cell autoimmunity in mice and confirm the existence of an analogous heart/med-LN/T cell axis in patients with MI.

Authors

Max Rieckmann, Murilo Delgobo, Chiara Gaal, Lotte Büchner, Philipp Steinau, Dan Reshef, Cristina Gil-Cruz, Ellis N. ter Horst, Malte Kircher, Theresa Reiter, Katrin G. Heinze, Hans W.M. Niessen, Paul A.J. Krijnen, Anja M. van der Laan, Jan J. Piek, Charlotte Koch, Hans-Jürgen Wester, Constantin Lapa, Wolfgang R. Bauer, Burkhard Ludewig, Nir Friedman, Stefan Frantz, Ulrich Hofmann, Gustavo Campos Ramos

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Figure 2

TCR-M cells selectively accumulate in the infarcted heart.

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TCR-M cells selectively accumulate in the infarcted heart. (A) Experimen...
(A) Experimental design and gating strategy. Thy1.1 TCR-M cells were transferred into Thy1.2 WT recipients prior to MI or sham operations. The contour plots are representative of the med-LNs 7 days after MI. The frequencies of TCR-M cells found in the si-LNs, med-LNs (heart-draining), and heart were assessed on (B) day 7 and (C) day 49 after MI. The accumulation index refers to the spleen-normalized frequencies. (D and F) 3D reconstruction of infarcted hearts (original magnification, ×5) on day 7 (D and E) and day 49 (F) after MI. The morphological information was obtained from the autofluorescence levels acquired in the green channel. The viable myocardium appears in bright green, and the necrotic myocardium appears in dark green. Scale bars: 300 μm. TCR-M cells (Thy1.1+) appear in magenta, and the yellow dotted lines indicate the infarct borders. (G–L) Frequency of CD44+ cells (G–I) and FOXP3+ cells (J–L) in the ENDO and TCR-M compartments harvested from different sites on day 7 after MI. The dotted lines indicate the baseline frequencies (pre-transfer) of CD44+ and FOXP3+ among TCR-M cells. The graphs display the group mean values (bars), the SEM, and the distribution of each individual value. (B and C) The green and magenta bars represent sham-operated and infarcted mice, respectively. (G–L) The green and magenta bars represent endogenous CD4+ T cells and TCR-M cells, respectively. The data were acquired in at least 2 independent experiments; MI (n = 7–23 mice) and sham (n = 3–12 mice). *P < 0.05, by 2-way ANOVA followed by Sidak’s multiple comparisons test. LV, left ventricle; RV, right ventricle; ND, not determined.