Myocardial infarction triggers cardioprotective antigen-specific T helper cell responses
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
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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Research Article Cardiology Immunology

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 5

Heart-specific CD4+ T cells activated in the MI context exert cardioprotective effects.

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Heart-specific CD4+ T cells activated in the MI context exert cardioprot...
(A) Experimental design: TCR-M cells (specific for the cardiac antigen MYCA614–629) and DO11.10 cells (specific for the irrelevant antigen OVA323–339) were adoptively transferred into DO11.10 mice prior to MI or sham operation, and the cardiac outcomes were monitored at the peak of the healing phase (day 7). (B) The infarct size and long parasternal axis (apex-aortic valve) were assessed by echocardiography. The (C) FAC, (D) ESA, and (E) EDA at the mid-papillary level were assessed by echocardiography. (F) Cardiac macrophages, defined as CD45+CD11b+Ly6G–CD64+ singlets, were stratified into 4 major subsets according to CCR2 and MHC-II expression, and the effects in DO11.10 versus TCR-M cells on each subset’s distribution were assessed (day 5). (G) The collagen area in scar tissue 5 days after MI in DO11.10- and TCR-M–transferred mice was quantified by Picrosirius red staining (PSR). (H) Immunofluorescence of collagen III and its quantification in scar tissue 5 days after MI in DO11.10- and TCR-M–transferred mice. Scale bars: 100 μM. The bar graphs display the group mean values (bars), the SEM, and the distribution of each individual sample. Statistical significance was determined by 2-tailed, unpaired t test. *P < 0.05 and **P < 0.01. The data from TCR-M (n = 5–10) and DO11.10 (n = 7–9) recipients were acquired in 3 experiments.