CD69 expression on regulatory T cells protects from immune damage after myocardial infarction
Rafael Blanco-Domínguez, Hortensia de la Fuente, Cristina Rodríguez, Laura Martín-Aguado, Raquel Sánchez-Díaz, Rosa Jiménez-Alejandre, Iker Rodríguez-Arabaolaza, Andrea Curtabbi, Marcos M. García-Guimaraes, Alberto Vera, Fernando Rivero, Javier Cuesta, Luis J. Jiménez-Borreguero, Alberto Cecconi, Albert Duran-Cambra, Manel Taurón, Judith Alonso, Héctor Bueno, María Villalba-Orero, Jose Antonio Enríquez, Simon C. Robson, Fernando Alfonso, Francisco Sánchez-Madrid, José Martínez-González, Pilar Martín
Rafael Blanco-Domínguez, Hortensia de la Fuente, Cristina Rodríguez, Laura Martín-Aguado, Raquel Sánchez-Díaz, Rosa Jiménez-Alejandre, Iker Rodríguez-Arabaolaza, Andrea Curtabbi, Marcos M. García-Guimaraes, Alberto Vera, Fernando Rivero, Javier Cuesta, Luis J. Jiménez-Borreguero, Alberto Cecconi, Albert Duran-Cambra, Manel Taurón, Judith Alonso, Héctor Bueno, María Villalba-Orero, Jose Antonio Enríquez, Simon C. Robson, Fernando Alfonso, Francisco Sánchez-Madrid, José Martínez-González, Pilar Martín
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Research Article Cardiology Immunology

CD69 expression on regulatory T cells protects from immune damage after myocardial infarction

Abstract

Increasing evidence has pointed to the important function of T cells in controlling immune homeostasis and pathogenesis after myocardial infarction (MI), although the underlying molecular mechanisms remain elusive. In this study, a broad analysis of immune markers in 283 patients revealed significant CD69 overexpression on Tregs after MI. Our results in mice showed that CD69 expression on Tregs increased survival after left anterior descending (LAD) coronary artery ligation. Cd69–/– mice developed strong IL-17+ γδT cell responses after ischemia that increased myocardial inflammation and, consequently, worsened cardiac function. CD69+ Tregs, by induction of AhR-dependent CD39 ectonucleotidase activity, induced apoptosis and decreased IL-17A production in γδT cells. Adoptive transfer of CD69+ Tregs into Cd69–/– mice after LAD ligation reduced IL-17+ γδT cell recruitment, thus increasing survival. Consistently, clinical data from 2 independent cohorts of patients indicated that increased CD69 expression in peripheral blood cells after acute MI was associated with a lower risk of rehospitalization for heart failure (HF) after 2.5 years of follow-up. This result remained significant after adjustment for age, sex, and traditional cardiac damage biomarkers. Our data highlight CD69 expression on Tregs as a potential prognostic factor and a therapeutic option to prevent HF after MI.

Authors

Rafael Blanco-Domínguez, Hortensia de la Fuente, Cristina Rodríguez, Laura Martín-Aguado, Raquel Sánchez-Díaz, Rosa Jiménez-Alejandre, Iker Rodríguez-Arabaolaza, Andrea Curtabbi, Marcos M. García-Guimaraes, Alberto Vera, Fernando Rivero, Javier Cuesta, Luis J. Jiménez-Borreguero, Alberto Cecconi, Albert Duran-Cambra, Manel Taurón, Judith Alonso, Héctor Bueno, María Villalba-Orero, Jose Antonio Enríquez, Simon C. Robson, Fernando Alfonso, Francisco Sánchez-Madrid, José Martínez-González, Pilar Martín

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Figure 1

Patients with MI have a strong peripheral CD69+ Treg response.

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Patients with MI have a strong peripheral CD69+ Treg response. (A) t-SNE...
(A) t-SNE plots of CD4+ T cells from PBLs from a representative healthy control and a patient with MI, considering the indicated markers measured by FACS. Color bars indicate the relative intensity of the markers. Dots represent individual cells. (B) Quantification of the percentages of CD4+ T cells and CD4+CD25+Foxp3+ Tregs in peripheral blood from healthy donors (n = 51) and patients with MI (n = 215) at the time of hospital admission. (C) Percentages of CD69+ Tregs and CD69– Tregs among total PBLs. (D) CD69 expression on Tregs, quantified as the percentage of CD69+ cells after gating on Tregs. Two groups of patients with MI were differentiated according to CD69 expression: patients with high levels of CD69 (High CD69), shown as black circles, and patients with low levels (Low CD69), shown as red circles. Representative histograms and percentages of CD69 expression on Tregs are shown. In B–D, data indicate the mean ± SEM, and significance was analyzed by Mann-Whitney U test. (E) Heatmap shows the levels of different cell populations analyzed by FACS and cardiac damage markers in patient with MI expressing high levels of CD69 and low levels of CD69. Each column represents 1 patient. Data were normalized by subtracting the mean and dividing by the SD. Color bar denotes the relative levels of each parameter, with black indicating high expression and red indicating low expression. Differences between patients with CD69hi and CD69lo expression were analyzed by Mann-Whitney U test; *P < 0.05, **P < 0.01, and ****P < 0.0001. (F) t-SNE plot was generated based on the percentages of cell populations shown in E and analyzed by FACS. Circles represent individual patients with MI. Black circles indicate patients with MI who had high CD69 expression, and red circles indicate patients with low CD69 expression.