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 2

CD69 deficiency worsens heart damage and decreases survival after MI in mice.

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CD69 deficiency worsens heart damage and decreases survival after MI in ...
(A) Survival curve of mice after LAD ligation (n = 23–29 MI mice, n = 11–20 sham-operated mice). Data were pooled from 5 independent experiments and were analyzed by long-rank (Mantel-Cox) test. (B) Kinetics of the percentage of body weight loss after LAD ligation (n = 9–17 mice). Data represent the mean ± SEM and were analyzed by 2-way ANOVA with Šidák’s multiple-comparison test. (C) Representative images of infarcted hearts collected after intravenous injection of Evans blue dye 2 days after surgery. (D) Heart weight was normalized to body weight and tibia length 2 days after LAD ligation (n = 3–4 sham-operated mice; n = 5–6 MI mice). Data are representative of 3 independent experiments and indicate the mean ± SEM. Statistical significance was analyzed by 1-way ANOVA with Tukey’s post hoc test. (E) Representative images of heart slices showing the AAR (negative for Evans blue dye) in the upper panels and the extent of necrosis (negative for TTC staining) in the lower panels. (F) Histological quantification of the percentage of the LV AAR and the percentage of infarct size (IS) (n = 5–6 mice). Data are expressed as the mean ± SEM and were analyzed by unpaired Student’s t test. (G) Time course of LV dysfunction according to the WMSI measured by echocardiography (n = 6–16 MI mice, n = 4–8 sham-operated mice). Data were pooled from 3 independent experiments, represent the mean ± SEM, and were 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.