Roles of T lymphocytes in defense against experimental acute pulmonary infection of mice with murine cytomegalovirus

The aim of this study together with the preceding study (Kimura et al., Bio med. Res. 21(3), 145-163, 2000) is to reveal the sequential barrier of host -defense factors to experimental acute pulmonary infection of mice with mur ine cytomegalovirus. Time course of virus load in lungs following an intrat racheal inoculation with the virus was divided into 4 phases: the inoculum- decreasing, phase I (0 h post-infection (p.i.)-18h p.i.), the virus-load in creasing, phase II (24h p.i.-48h p.i.), the plateau of virus-load, phase II I (2d p.i.-14d p.i.), and the slow virus-clearance, phase IV (14d p.i.-24d- 28d p.i). The viral-antigen producing cells were detectable in phase III ex clusively in the cavity side of alveoli in the histological sections of lun gs. There was no histologically detectable inflammation both in the alveola r cavity and in the interstitium of the lungs. The number of T cells recove rable from lungs increased only to a small extent both in whole lungs and i n the bronchoalveolar space. CD8(+) T cells isolated from whole lungs durin g the period of time spanning 5d p.i.-21d p.i. however, had a readily-detec table immediate ex vivo CTL activity specific to the known dominant epitope in the immediately early gene product of the virus and a fraction of 20-40 % of CD8(+) T cells were producing IFN-gamma. The results of in vivo cell-d epletion and cytokine-depletion experiments suggest that each of CD4(+) T c ells and CD8(+) T cells alone play a role in the slow but substantial reduc tion of virus load in the lungs and that IFN-gamma also plays an antiviral role in phase IV. The results of double depletion experiments suggest that CD4(+) T cells and CD8(+) T cells synergistically play roles in prevention of a progressive increase in virus load in lungs beyond the plateau caused by expansion of the infection sites in the alveolar cavities and by infecti on of the interstitium of the lung. Taking together with the results of the preceding study, we suggest the frame of the sequential barrier to the pri mary pulmonary infection with the virus as follows. Phase I, alveolar macro phages; phase II, alveolar macrophages; the early phase III, alveolar macro phages; the late phase III, alveolar macrophages, CD8(+) T cells alone, and CD4(+) T cells and CD8(+) T cells in combination; and phase IV, CB4(+) T c ells alone, CD8(+) T cells alone, and CD4(+) T cells and CD8(+) T cells in combination. We suggest that, in defense against infection of the lung with a slowly-reproducing and mildly-cytotoxic virus like murine cytomegaloviru s, a nonspecific defense factor with a low tissue-toxicity like macrophages plays more important role than an antigen-specific and clonal-expansion de pendent defense factor like T cells, in order to avoid a life-threatening o bstruction of normal functioning of the lung due to long-lasting inflammati on.