Abstract
Purpose: :
The classic paradigm for CD4+ T-cell differentiation has defined two subsets of helper CD4+ T cells, Th1 cells and Th2 cells. A new CD4+ T-cell subset (Th17 cells) has been recognized that uniquely produces interleukin-17 (IL-17). While IL-17 plays a role in autoimmunity, its role in virus infection and HIV/AIDS progression remains controversial. We therefore performed a series of experiments to investigate the possible contribution of IL-17 to the pathogenesis of experimental cytomegalovirus (CMV) retinitis in mice with MAIDS, a clinically relevant animal model of retrovirus-induced immunosuppression.
Methods: :
To determine production of IL-17 during progression of MAIDS, splenic cells were collected from C57BL/6 mice with MAIDS of 4, 6, 8, 10, 12, and 14-weeks duration. To explore IL-17 production vis-à-vis development of retinitis, splenic cells and whole eyes of MAIDS-10 animals were collected at 3, 6, and 10 days after subretinal injection with either murine CMV (MCMV) or virus maintenance medium only. To investigate impact of acute systemic MCMV infection on IL-17 production, splenic cells were collected from normal mice or MAIDS-10 mice injected with a sub-lethal dose of virus. Quantification of IL-17 mRNA levels for splenic cells and whole eyes from all animals was accomplished by real time RT-PCR assay.
Results: :
Progression of MAIDS was associated with a concomitant increase in splenic IL-17 mRNA levels that was significantly high when animals became susceptible to MCMV retinitis (MAIDS-8). Surprisingly, MCMV-infected whole eyes collected from MAIDS-12 animals failed to show an increase in IL-17 mRNA levels above that observed in mock-infected eyes. Systemic MCMV infection of both MAIDS and normal mice resulted in a significant 25-fold decrease in splenic IL-17 mRNA levels when compared with uninfected controls.
Conclusions: :
In addition to a shift in systemic cytokine production from a Th1 profile to a Th2 profile, retrovirus-induced immunosuppression during MAIDS is associated with a dramatic increase in systemic IL-17 production, an increase not observed in MCMV-infected eyes susceptible to retinal disease. In fact, MCMV infection may downregulate Th17 cells during systemic infection. We conclude that direct contribution of IL-17 to the pathogenesis of MAIDS-related MCMV retinitis is minimal although indirect mechanisms are possible.
Keywords: cytomegalovirus • retinitis • microbial pathogenesis: experimental studies