THE ROLE OF CD8(-LYMPHOCYTES IN COXSACKIEVIRUS B3-INDUCED MYOCARDITIS() T)

Coxsackievirus infections have previously been shown to cause acute or chronic myocarditis in humans, and several mouse models have been est ablished to study the pathology of this disease. Myocardial injury may result from direct viral effects and/or may be immune mediated, To de termine the relative roles of these processes in pathogenesis, we have compared coxsackievirus B3 (CVB3) infections of normal and immuno-com promised transgenic knockout (ko) mice, CVB3 was able to infect all st rains used (C57BL/6, CD4ko, and beta-microglobulin ko [beta 2Mko]), an d following intraperitoneal injection, two disease processes could be distinguished, First, the virus caused early (3 to 7 days postinfectio n) death in a viral dose dependent manner, Immunocompetent C57BL/6 mic e were highly susceptible (50% lethal dose = 70 PFU), while immunodefi cient transgenic ko mice were less susceptible, showing 10- and 180-fo ld increases in the 50% lethal dose (for CD4ko and beta 2Mko mice, res pectively), Second, a histologic examination of surviving CD4ko mice a t 7 days postinfection revealed severe myocarditis; the inflammatory i nfiltrate comprised 40 to 50% macrophages, 30 to 40% NK cells, and 10 to 20% CD8(+) T lymphocytes, The infiltration resolved over the follow ing 2 to 3 weeks, with resultant myocardial fibrosis, In vivo depletio n of CD8(+) T lymphocytes from these CD4ko mice led to a marked reduct ion in myocarditis and an increase in myocardial virus titers. beta 2M ko mice, which lack antiviral CD8(+) T cells, are much less susceptibl e to early death and to the development of myocarditis. We conclude th at our data support a strong immunopathologic component in CVB3-induce d disease and implicate both CD4(+) and CD8(+) T cells, Compared with immunocompetent animals, (i) mice lacking CD4(+) T cells (CD4ko) were more resistant to virus challenge, and (ii) mice lacking CD8(+) T cell s (beta Mko and in vivo-depleted CD4ko) showed enhanced survival and a reduced incidence of the later myocarditis. Nevertheless, the picture is complex, since (iii) removal of the CD4(+) component, while protec ting against early death, greatly magnified the severity of myocarditi s, and (iv) removal of the CD8(+) cells from CD4ko mice, although prot ecting against early death and later myocarditis, led to markedly incr eased virus titers in the heart, These data underscore the complex bal ance between the costs and benefits of effective antiviral immune resp onses.