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 5

Expression of CD39 by CD69+ Tregs after MI mediates the inhibition of γδΤ cells.

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Expression of CD39 by CD69+ Tregs after MI mediates the inhibition of γδ...
(A) Sorted wild-type γδT cells were cocultured for 24 hours with Cd69+/+ or Cd69–/– sorted Tregs at the indicated γδT/Treg ratios. Apoptosis of γδT cells, represented as the fold increase of annexin V+ (Ann. V+) γδT cells versus γδT cells alone (ratio 1:0) (n = 4–10). A representative zebra plot of the 1:0.5 ratio, gated on γδT cells is shown. (B) Inhibition of IL-17A production by γδT cells, plotted as the fold change of IL-17A+ γδT cells for each ratio versus the 1:0 ratio (n = 6–12). Representative zebra plots of the 1:0.5 ratio, gated on γδT cells, are shown. Data in A and B were pooled from 4 independent experiments. Data indicate the mean ± SEM. Statistical significance was determined by 2-way ANOVA with Sidak’s multiple-comparison test. Significant P values are shown (black for Cd69+/+ Tregs and red for Cd69–/– Tregs). (C) CD39 expression on Tregs in PBLs, mediastinal lymph nodes (Med-LN), and heart was measured by FACS, 2 days after MI (n = 4–5). Data indicate the mean ± SEM. Statistical significance was determined by 1-way ANOVA with Tukey’s post hoc test. (D) Extracellular ATP was measured in the supernatant of isolated Tregs, in the presence or absence of ARL 67156 (ARL) at the indicated time points after ATP supplementation (n = 3–5). Data are from 1 representative independent experiment of 4 experiments and indicate the mean ± SEM. Statistical significance was determined by mixed-effects 2-way ANOVA with Šidák’s multiple-comparison test. (E) IL-17A production by sorted γδT cells in the presence of Tregs and/or ARL 67156, fold change versus the percentage of IL-17A+ γδT cells alone (n = 3–7). Data are representative of 3 independent experiments and indicate the mean ± SEM. Statistical significance was determined by 2-way ANOVA with Šidák’s multiple-comparison test. (F) Quantification of Ahr, Cyp1b1, and Entpd1 mRNA levels in Tregs by qPCR (n = 6–7). Data were pooled from 2 independent experiments and represent the mean ± SEM. Statistical significance was determined by unpaired Student’s t test.