Project Summary/Abstract People lacking CD4+ T cells due to acquired or primary immunodeficiency usually become ill due to infection with microbes such as Mycobacteria, Salmonella, and Cryptococcus that persist in the phagosomes of phagocytes. Phagosomal pathogens are normally controlled by IFN-γ-producing Th1 cells in granulomas that form at the initial site of infection. For unknown reasons, however, the Th1 cells can not eliminate the microbes from the granulomas. The regulatory mechanisms that allow Th1 cells to control these infections in granulomas without eliminating them are not understood. This knowledge gap has prevented the development of effective vaccines for phagosomal pathogens that now afflict billions of people. The goal of this project is to close this gap by using state of the art cell tracking and mouse genetic techniques to study how Th1 cells specific for peptides from the prototypical phagosomal pathogen Salmonella enterica and associated granulomas develop during infection. We will build on our finding that S. enterica infection drives the formation of two types of Th1 cells expressing different chemokine receptors by testing the idea that persistent infection and thymic production of new T cells drives a cycle in which one Th1 population generates the senescent and cytotoxic other one. We will use fluorescent bacteria to determine whether these Th1 populations kill the bacteria in phagocytes or kill the phagocytes that harbor the bacteria. We will also determine whether these processes occur in macrophage-rich granulomas and what role Th1 cells play in granuloma formation by manipulating the Th1 cells and granuloma macrophages. The potential payoff from this project is an understanding of this unusual form of non-sterilizing microbial control that protects immunocompetent individuals from some of the deadliest pathogens but has been impossible to harness via vaccination.