Tracking CD4+ Memory T Cells in Vivo

Project Summary/Abstract The adaptive immune system protects the host from a second infection by generating infection-specific lymphocytes called memory cells. Memory cells come from a much larger population of effector cells, which are generated from rare naïve cells that proliferate after antigen binds to their antigen receptors. The objective of this project is to understand CD4+ memory T cell formation in the context of a persistent infection with the phagosomal pathogen Salmonella enterica serovar Typhimurium (Se) that is controlled by CD4+ T cells. Se infection generates a large population of interferon-gamma-producing CD4+ T cells (Th1 cells) that is stably maintained but declines slowly if infection is eliminated. Although the vast majority of cells in the Th1 population have a quiescent memory cell-phenotype during persistent infection, the numerical stability of the population is associated with intermittent bursts of antigen-driven proliferation by a small number of cells. The Th1 population consists of two IL-12-dependent subsets, one expressing CXCR3 and the other CX3CR1, both of which play roles in Se protection. We hypothesize that the vast majority of CXCR3+ Th1 cells are maintained by IL-7 like true memory cells but interact intermittently with rare infected macrophages and undergo T cell receptor-driven proliferation to produce terminally differentiated CX3CR1+ cells and more CXCR3+ Th1 memory cells. We posit that the CXCR3+ Th1 cells that undergo repeated cycles of intermittent stimulation become capable of indefinite survival without the infection. Here, we will test these hypotheses using adoptive transfer and cell ablation experiments and use the results to design vaccines that produce immunity without a persistent infection. Completion of these aims would yield basic information about CD4+ memory T cells in contexts where they are critical for immunity and give clues about how to make vaccines for some of the world’s most deadly pathogens.