Inflation and Long-Term Maintenance of CD8 T-Cells Responding to a Latent Herpesvirus Depend upon Establishment of Latency and Presence of Viral Antigens

摘要

Following the priming and contraction phases of the T-cell response, latent persistent herpesviruses lead to an accumulation of large pools of virus-specific CD8 T-cells, also known as memory inflation (MI). The mechanism of this inflation is incompletely understood, largely because molecular reactivation of these viruses in vivo and its impact upon T-cell biology have not been resolved in mice, and because the relevant observations in humans remain, by necessity, correlative. Understanding these processes is essential from the standpoint of the proposed critical role for latent herpesviruses in aging of the immune system. We studied the causes of memory CD8 T-cell accumulation following systemic HSV-1 administration, as a model of widespread latent viral infection in humans. Direct role of viral latency and Ag-specific restimulation in driving accumulation and maintenance of inflated CD8 T-cells, and strongly suggestive role of viral reactivation in that process, were shown by: (i) lack of MI in the absence of established latency; (ii) prevention or delay of MI with drugs that curtail viral replication; and (iii) abrogation of MI by transfer of inflated T-cells into virus-free environment. These results strongly suggest that periodic, subclinical reactivations of a latent persistent virus cause dysregulation of memory CD8 T-cell homeostasis similar to the one in humans. Moreover, results with antiviral drugs suggest that this approach could be considered as treatment modality to maintain T-cell diversity and/or function in the old age.