The mammalian T cell response to Salmonella enterica serovar Typhimurium
The major focus of our research is on the role of mammalian T cells in adaptive immunity to Salmonella enterica serovar Typhimurium (S. Typhimurium), an intracellular bacterial pathogen. We use a combination of cellular and molecular approaches to determine how S. Typhimurium infection and S. Typhimurium gene expression shape and influence development of the T cell response.
Inflammatory cells of the innate immune system, such as macrophages and neutrophils, provide a first line of defense against S. Typhimurium; however, ultimate clearance of S. Typhimurium requires lymphocytes of the adaptive immune system. During infection, T cells are a key lymphocyte subset required for eliminating S. Typhimurium.
A crucial step in inducing a T cell response is T cell priming; the activation, proliferation, and differentiation of naïve T cells following their initial encounter with antigen displayed on the surface of professional antigen presenting cells such as dendritic cells. As T cells proliferate and differentiate into effector T cells, they can acquire the ability to lyse infected cells or secrete cytokines that help resolve infection. While T cells are important in adaptive immunity to S. Typhimurium, development of T cell-mediated adaptive immunity to S. Typhimurium has been described as slow and inefficient. We have been exploring why development of T cell-mediated adaptive immunity to S. Typhimurium is slow and inefficient, and whether S. Typhimurium play an active role in inhibiting development of protective immunity.
We previously showed that T cells failed to proliferate in response to antigen-laden dendritic cells when S. Typhimurium were present. Dendritic cells are the most important professional antigen presenting cells, and are a central link between the innate and adaptive immune system. We found that S. Typhimurium killed dendritic cells, preventing presentation of antigen to T cells. However, when we used mutant S. Typhimurium that could not kill dendritic cells, we found that the T cells remained unable to proliferate. These results led us to conclude that while dendritic cell killing may contribute to the lack of T cell proliferation, dendritic cell killing alone was not responsible for the lack of T cell proliferation. We further showed that, even in the absence of dendritic cells, S. Typhimurium had an inhibitory effect on T cells, blocking their proliferation. Most recently, we showed that S. Typhimurium downmodulate expression of the T cell receptor beta chain (TCRb), a molecule that is required for antigen recognition and T cell function.
Our long-term objective is to dissect the means by which S. Typhimurium interfere with development of T cell-mediated adaptive immunity. Our research should provide new insight into how microbial pathogens like S. Typhimurium avoid clearance by the mammalian immune system in order to replicate within mammalian hosts.