T helper cells with specificity for an antigen in cardiomyocytes promote pressure overload-induced progression from hypertrophy to heart failure

Carina Gröschel,Andrew H Lichtman,Ralf Dressel,Michael Didié,Karl Toischer,Leslie Elsner,Charlotte Röhrborn,André Sasse,Gertrude Bunt,Gerd Hasenfuß,Sebastian Monecke,Wolfram-Hubertus Zimmermann,Vanessa Kruse

doi:10.1038/s41598-017-16147-1

Abstract

We investigated whether CD4+-T cells with specificity for an antigen in cardiomyocytes promote the progression from hypertrophy to heart failure in mice with increased pressure load due to transverse aortic constriction (TAC). OT-II mice expressing a transgenic T cell receptor (TCR) with specificity for ovalbumin (OVA) on CD4+-T cells and cMy-mOVA mice expressing OVA on cardiomyocytes were crossed. The resulting cMy-mOVA-OT-II mice did not display signs of spontaneous autoimmunity despite the fact that their OVA-specific CD4+-T cells were not anergic. After TAC, progression to heart failure was significantly accelerated in cMy-mOVA-OT-II compared to cMy-mOVA mice. No OVA-specific antibodies were induced in response to TAC in cMy-mOVA-OT-II mice, yet more CD3+ T cells infiltrated their myocardium when compared with TAC-operated cMy-mOVA mice. Systemically, the proportion of activated CD4+-T cells with a Th1 and Th17 cytokine profile was increased in cMy-mOVA-OT-II mice after TAC. Thus, T helper cells with specificity for an antigen in cardiomyocytes can directly promote the progression of heart failure in response to pressure overload independently of autoantibodies.

Highlights

Heart failure is among the most frequent causes of morbidity and mortality in western countries with an estimated prevalence of more than 37 million individuals globally[1]
Indirect evidence suggested that the effect of CD4+-T helper cells on cardiac function after transverse aortic constriction (TAC) depends on antigen recognition because T cell receptor (TCR)-transgenic OT-II mice, which possess predominantly CD4+-T helper cells specific for ovalbumin (OVA), an antigen absent in mice, did not show progression into heart failure after TAC15
Several recently published studies revealed a critical role of T cells in the progression of pressure overload-induced heart failure[15,16,17,18]

Summary

Introduction

Heart failure is among the most frequent causes of morbidity and mortality in western countries with an estimated prevalence of more than 37 million individuals globally[1]. Since OT-II mice, which have T helper cells with specificity for OVA20, were reported to be protected from progression into heart failure after TAC15, we asked whether the deterioration of heart function would be accelerated in OT-II mice that express OVA in cardiomyocytes. To obtain such mice, we crossed OT-II with cMy-mOVA mice[21], which express OVA, fused to the transmembrane part of the human transferrin receptor at the plasma membrane of cardiomyocytes driven by a murine cardiac α-myosin heavy-chain (αMHC) promoter. T helper cells with specificity for an antigen expressed in cardiomyocytes directly exert negative effects on cardiac function in this model

Methods

Results

Conclusion