Author

Anna Lang

Date

September 2007

Document Type

Dissertation

Degree Name

Ph.D.

Institution

Oregon Health & Science University

Abstract

Certain viruses are capable of establishing lifelong persistent infections within vertebrate hosts. Such infections can be chronic or latent, and accumulating evidence suggests that they provide ongoing antigenic stimulation to memory T cells throughout lifetime. In addition, infection with some persistent viruses were implicated in driving inflammation-driven expansions of bystander T cells. Both antigen-driven and bystander stimulation ofT cells can be expected to affect the composition and diversity of the T cell pool. These processes were suggested to drive the age-associated changes in maintenance of stable T cell pool, contributing to the process of immunosenescence. In this thesis I examined the impact of both lifelong viral infections as well as aging on the maintenance of systemic CD8+ T cells over lifetime in a mouse model of Herpes Simplex Virus type 1 (HSV -1) and murine cytomegalovirus (MCMV) infection. Both viruses establish latent infections, however recent evidence implies that infection with MCMV is characterized by frequent viral reactivation, as inferred from ongoing expansion of MCMV -specific CD8+ T cells over the timecourse of infection, a process termed memory inflation. Less is known about the effect of HSV -1 infection on maintenance of antiviral memory CD8+ T cell. Until recently, HSV -1 infection in mice was believed to be truly latent and not associated with ongoing antigen presentation. However, evidence gathered over the last decade implies that this may not be the case and that reactivation of HSV -1 from latency in mice is more frequent than previously thought. I investigated both primary and memory CD8+ T cell response to HSV-1, with special focus on involvement of antigen in maintenance of the memory population. I found that the frequency and numbers of HSV -specific memory CD8+ T cells depend on infection route, the extent of initial viral spread and the extent of viral reactivation from latency. Systemic HSV-1 infection correlated with greater viral spread and early onset of CD8+ T cell memory inflation, whereas localized infection resulted in limited viral spread and absence of virus-driven memory CD8+ T cell expansion over the course of latent infection. The extent of memory inflation following systemic infection was antigen-driven, as blocking viral replication from latency could prevent it. Therefore, under certain conditions HSV-1 was able to drive CD8+ T cell memory inflation in mice. Despite the ability to stimulate CD8+ T cell memory inflation, lifelong HSV -1 or MCMV infection alone was not associated with significant constriction of the TCR repertoire diversity or phenotypic changes among CD8+ T cells in old infected mice. However, combination of both virus-related and virus-independent effects influenced the TCR composition and phenotype of the aging CD8+ T cell pool. In summary, in this thesis I present evidence that both virus-driven and virus independent aging-associated mechanisms contribute to changes in the T cell pool homeostasis over lifetime contributing to the state of immunosenescence. Onset of immunosenescence correlates with increased morbidity and mortality in the elderly and understanding the mechanisms of its development and maintenance should aid in designing therapeutic strategies to prevent it.

Identifier

doi:10.6083/M4V9863J

School

School of Medicine

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