Susceptibility to myocarditis is dependent on the response of alphabeta T lymphocytes to coxsackieviral infection.
Viral myocarditis is an important cause of heart failure and dilated cardiomyopathy. T lymphocytes are implicated in myocardial damage in murine models of coxsackievirus B3 (CVB3) myocarditis. We used knockout mice lacking CD4 (CD4(-/-)), CD8 (CD8(-/-)), both coreceptors (CD4(-/-)CD8(-/-)), or the T-cell receptor beta chain (TCRbeta(-/-)) to address the contribution of T-cell subpopulations to host susceptibility to CVB3 myocarditis. Severity of disease was magnified in CD8(-/-) mice but attenuated in CD4(-/-) mice, consistent with a pathogenic role for CD4(+) lymphocytes. Elimination of both CD4 and CD8 molecules from T lymphocytes by genetic knockout better protected mice from myocarditis, demonstrating that both CD4(+) and CD8(+) T cells contribute to host susceptibility. The same benefit occurred in TCRbeta(-/-) mice, with prolonged survival and minimal myocardial disease observed after CVB3 infection. Elevated interferon-gamma and decreased tumor necrosis factor-alpha expression are associated with attenuated myocardial damage in CD4(-/-)CD8(-/-) mice. These results show that the presence of TCRalphabeta(+) T cells enhances host susceptibility to myocarditis. The severity of myocardial damage and associated mortality are dependent on the predominant T-cell type available to respond to CVB3 infection. One mechanism by which CD4(+) and CD8(+) T-cell subsets influence the pathogenesis of myocarditis may involve specific cytokine expression patterns.
Opavsky
M A
MA
Centre for Cardiovascular Research, The Toronto Hospital, University of Toronto, Toronto, Ontario, Canada.
Penninger
J
J
Aitken
K
K
Wen
W H
WH
Dawood
F
F
Mak
T
T
Liu
P
P
D000818:Animals; D015704:CD4 Antigens / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D016827:CD8 Antigens / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D003384:Coxsackievirus Infections / Q000401:mortality / Q000503:physiopathology* / Q000821:virology; D016207:Cytokines / Q000378:metabolism; D004198:Disease Susceptibility; D004770:Enterovirus / Q000302:isolation & purification; D007107:Immune System / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D008822:Mice, Transgenic / Q000235:genetics; D009205:Myocarditis / Q000473:pathology / Q000503:physiopathology / Q000821:virology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000502:physiology*
D015704:CD4 Antigens; D016827:CD8 Antigens; D016207:Cytokines; D016693:Receptors, Antigen, T-Cell, alpha-beta