Graphic_Ben.jpg

The power of the adaptive immune system lies in its ability to elicit a stronger response upon repeated pathogen exposure through the generation of immunological memory. This facet of the immune system is the driving mechanism behind the success of vaccination. Thus, there is much interest in understanding the prerequisites of how memory is formed in order to create more effective vaccines. In particular, CD8 T cell memory is critical for controlling viral infections and tumors, and the CD8 T cell compartment comprises heterogeneous and complementary cell populations, which are differentiated by lineage, function and location (compartmentalization) within the tissues of the body. For example, central memory (Tcm) CD8 T cells circulate through the blood and lymphoid tissues and proliferate during secondary challenge to feed into an effector memory (Tem) pool, which circulates through blood and peripheral tissues. Resident memory (Trm) are restricted in their localization to peripheral mucosal or barrier sites of pathogen entry. The conditions under which these diverse populations differentiate from effector precursors remain an intense area of research and a focus of our lab. In particular, we are interested in how cytokine signaling during activation and the subsequent CD8 effector response could affect downstream memory commitment.  The cytokine TGFβ has been identified as a negative regulator of the CD8 effector response and our goal is to understand how this molecule may contribute to the overall process of memory generation. To do this, we are employing various mouse genetic mutants in which TGFβ signaling has been disrupted in CD8 T cells at specific time points in their differentiation pathway, including before and after activation. By challenging these animals with model pathogens such as Lymphocytic choriomeningitis virus (LCMV) and Listeria monocytogenes (LM), we can determine and study the phenotype and function of Tcm and Tem populations generated in the absence of TGFβ signaling. The results of these studies may prove useful in designing better vaccines that generate specific desired memory populations.