CD69 expression on regulatory T cells protects from immune damage after myocardial infarction
Rafael Blanco-Domínguez, … , José Martínez-González, Pilar Martín
Rafael Blanco-Domínguez, … , José Martínez-González, Pilar Martín
Published September 6, 2022
Citation Information: J Clin Invest. 2022;132(21):e152418. https://doi.org/10.1172/JCI152418.
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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 3

Treg and IL-17A responses in the blood of mice after LAD ligation.

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Treg and IL-17A responses in the blood of mice after LAD ligation. (A) F...
(A) Fold increase of the percentages of wild-type CD69+ Tregs, wild-type CD69– Tregs, and Cd69–/– Tregs among CD4+ cells in peripheral blood 1 day after LAD ligation or sham surgery, compared with the percentages on day 0 (dotted line). Representative density plots of Tregs on day 0 and day 1 after MI are shown on the right (n = 10–20). Histograms indicate the mean ± SEM, and data were analyzed by 1-way ANOVA with Tukey’s post hoc test. (B) Kinetics of IL-17A+ cells in peripheral blood after surgery, expressed as a percentage of total cells. (C) Left: Representative dot plots of IL-17A+ cells, with the percentages of total cells indicated in the outlined box. Right: Representative dot plots showing the main cell populations positive for IL-17A. (D). Kinetics of the percentages of γδT cells and IL-17+ γδT cells in peripheral blood after LAD ligation or sham surgery. (E) Representative density plots of γδT cells in peripheral blood, with the percentages of cells indicated in the outlined box. Data in B and D are representative of 4 independent experiments and indicate the mean ± SEM (n = 6–10). Statistical significance was analyzed by 2-way ANOVA with Šidák’s multiple-comparison test. Asterisks denote differences between MI and sham-operated mice (light gray for Cd69+/+ mice, light red for Cd69–/– mice); ampersands denote differences between Cd69+/+ and Cd69–/– MI mice; plus signs denote differences between each day and day 0. +/&P < 0.05, **/++/&&P < 0.01, ***/&&&P < 0.001, and ++++/&&&&P < 0.0001.