The immune system acquires much of its antigen experience during childhood and early adulthood, either through infection or vaccination. While the pools of memory CD8+ T cells generated at this time persist for the life of the individual, there is a progressive loss in their capacity to mediate protective immunity. However, the relationships between memory CD8 + T cell subpopulations, protective immunity, and increasing age are poorly understood. In this proposal, we take advantage of well-characterized mouse models of respiratory virus infection to study memory CD8 + T cells in aged mice. Preliminary data show that the composition of memory T cell pools undergoes profound changes in phenotype, function, and anatomical distribution as the animal ages. First, there is a progressive accumulation of antigen-specific memory CD8+ T cells expressing a CD62L[high]/CD43[low] phenotype. These cells have a reduced capacity to proliferate in vitro and account for the vast majority of memory CD8+ T cells in aged animals. Second, there is a specific loss of effector-memory CD8+ T cells from the lung with increasing time post infection. These cells are virtually absent from the lungs of aged animals. Based on these data, we speculate that the loss of cellular recall responses to respiratory virus infections in aged animals reflects accumulated changes in the distribution and function of memory T cell pools. To address the impact of age on CD8 + T cell memory, we will pursue the following three aims: (i) We will determine how the distribution and turnover of distinct memory CD8 + T cell subsets change with increasing age and antigen re-exposure. Studies will focus on the role of homeostatic proliferation and subsequent antigen exposure on the age related changes in the distribution of memory CD8+ T cell subpopulations. (ii) We will determine the functional status of distinct memory CD8 + T cell subsets. In particular, we will determine their capacity to mediate control of a secondary virus infection in vivo, which is a highly stringent assay of memory CD8+ T cell efficacy. Studies will focus on the CD62L[high]/CD43[low] subset of cells that accumulate in aged mice. (iii) We will determine whether memory T cell subpopulations induced by vaccines differ in their heterogeneity and stability. Taken together, these studies will identify critical parameters for the development of vaccines designed to induce cellular immunity that retains efficacy with increasing age.
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