Regulation and maintenance of antiviral T cells during acute and chronic viral infections.

摘要

Antiviral immunity results from the concerted actions of a variety of leukocytes, each playing their designated role at the proper time and place. Specifically, naive CD8 T cells are primed by matured dendritic cells presenting viral peptide epitopes that have received a maturation stimulus from primed, antigen-specific CD4 T cells. We have created strains of transgenic mice that, upon activation by mitogens in vitro or following infection in vivo, are permanently marked with innocuous reporter proteins. We report here on the population dynamics, turnover, antigen specificity, phenotype, and effector functions of the virus-specific CD8 T cells in reporter protein-marked and unmarked populations. Additionally, we have investigated the mechanisms by which some strains of LCMV are able to establish persistent infections and anergize the normally sterilizing CD8 T cell immune response. We find that IL-10 produced during the early stages of the infections plays a role in the progressive loss of effector functions by CD8 T cells. A short course of anti-IL-10 treatments were unable to restore complete functionality to the T cells, indicating that other mechanisms are operating to bring about T cell anergy. Finally, we have also developed a protocol utilizing injections of anti-CD137 that elicits tolerogenic dendritic cells. Our tolerizing protocol was validated in a model of experimental LCMV infection of mice. We demonstrate that injections of anti-CD137 within 24 hours of LCMV infection resulted in an abortive T cell response, long-term T and B cell tolerance, and a persistent viral infection with a strain of LCMV that is normally cleared in 8 days. Taken together, these data from the acute and persistent viral infections indicate that there are critical events occurring very soon after infection that influence the coarse of the adaptive immune response. These early events can be harnessed to improve viral control in the case of IL-10 blockade during a persistent viral infection, or induce tolerance in the case of cross-linking CD 137 on the surface of dendritic cells.