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 7

High CD69 expression in patients early after MI is associated with a decreased risk of developing HF.

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High CD69 expression in patients early after MI is associated with a dec...
(A) After 2.5 years of clinical follow-up, patients from the main study cohort were stratified according to whether or not they developed HF. CD69 expression on Tregs at the time of hospital admission for acute MI in patients who developed HF (n = 7) or did not develop HF (n = 180). Data were analyzed by Mann-Whitney U test. (B) Percentage of patients with low or high levels of surface CD69 expression on Tregs, measured by FACS in the main study cohort. The P value was calculated using a χ2 test. (C) Frequency of patients with low or high levels of CD69 mRNA expression, measured by qPCR in the main study cohort (the mean normalized CD69 2–ΔCt values were used to discriminate patients expressing low or high levels of CD69). (D) Correlation of FOXP3 and CD69 mRNA expression in PBLs from individuals in the main study cohort. Spearman’s correlation coefficient (r) and P values are shown. (E) CD69 mRNA levels measured by qPCR in total PBLs from the independent validation cohort of patients (n = 75 with no HF and n = 9 with HF). Data were analyzed by Mann-Whitney U test. (F) Frequency of patients with low or high levels of CD69 mRNA, measured by qPCR in the validation cohort (the mean normalized CD69 2–ΔCt values were used to discriminate patients with low or high CD69 expression). The P value was calculated using a χ2 test. (G) Correlation of FOXP3 and CD69 mRNA expression in PBLs from individuals in the validation cohort. Spearman’s correlation coefficient (r) and P values are shown.