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Cardiovascular Research 2000 45(3):579-587; doi:10.1016/S0008-6363(99)00267-9
© 2000 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

T cells expressing the {gamma}{delta} T cell receptor induce apoptosis in cardiac myocytes

Sally A. Huber*

Department of Pathology, University of Vermont, 55A South Park Drive, Colchester, VT 05446, USA

* Corresponding author. Tel.: +1-802-656-8944; fax: +1-802-656-8965 shuber{at}salus.uvm.edu

Objective: Enterovirus infections are major etiological factors in myocarditis and dilated cardiomyopathy. Using an experimental murine model of this disease, previous studies have shown that myocarditis susceptibility depends upon activation of T lymphocytes expressing the {gamma}{delta} T cell receptor (TcR), and that only mouse strains which accumulate {gamma}{delta} T cells in the myocardium show apoptosis of myocytes or evidence of dilated cardiomyopathy-like disease. The objective of the present studies is to demonstrate that {gamma}{delta} T cells directly induce greater Fas-dependent apoptosis of cultured myocytes than T cells expressing the {alpha}β TcR. Methods: Bl.Tg.E{alpha} mice were infected for 7 days with coxsackievirus B3 (CVB3). Hearts were removed and were either formalin-fixed, sectioned and stained with hematoxylin and eosin for inflammation, and using TdT-TUNEL for apoptosis, or were minced and collagenase digested for isolation of {gamma}{delta}+ and {alpha}β+ T cells using immunomagnetic bead separation. Neonatal cultures of cardiac myocytes were isolated from mice less than 2 days old by collagenase and pancreatin digestion, and were either untreated or infected with virus. Levels of Fas (CD95) were measured using FITC-conjugated hamster anti-mouse Fas monoclonal antibody and flow cytometry. Susceptibility of myocytes to Fas-dependent killing was measured by 51Cr-release by labeled myocytes incubated for 4 h on either 3T3-mock or 3T3-FasL transfected cell monolayers. Killing by T cells was also measured in a 4 h 51Cr-release assay. Fas-dependent and perforin-dependent cytotoxicity was determined by specific blocking using either Fas-Fc or concanamycin A. Results: Virally infected myocyte cultures showed significantly enhanced Fas expression compared to uninfected cells, with maximal upregulation of Fas occurring 18–24 h after virus infection. Both infected and uninfected myocytes were selectively killed by FasL-transfected 3T3 cells but not by mock control cells. Approximately 38% of CD3+ lymphocytes isolated from the heart express the {gamma}{delta} TcR with the remainder expressing the {alpha}β TcR. Both {gamma}{delta}+ and {alpha}β+ T cells lysed myocyte targets. Blocking studies indicate that {gamma}{delta}+ T cells induced predominantly Fas-mediated killing, while {alpha}β+ cell produced more perforin-mediated death, although these effectors were capable of Fas-dependent killing as well. Conclusions: These studies demonstrate that T cells expressing the {gamma}{delta} TcR are more effective mediators of myocyte apoptosis than {alpha}β+ T cells in vitro and suggests that these effectors may be primarily responsible for myocardial injury associated with dilated cardiomyopathy-like signs during coxsackievirus B3-induced myocarditis.

KEYWORDS Apoptosis; Cell culture/isolation; Immunology; Myocarditis; Myocytes


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