Fundamental characteristics of the adaptive immune system are the antigen-driven development of effector cells with enhanced functional capabilities and the development of long-term memory. While there have been rapid recent advances in our understanding of lineage relationships and mechanisms that control the emergence and maintenance of CDS T cell memory, our understanding of relationships between CD4 T cell effector differentiation and memory is limited. The long-term goal of this project is to define lineage relationships in a clonal CD4 T cell response during the antigen-driven transition from naive to effector and memory cell specification, with a view towards understanding the mechanisms that control them. The experimental approach is to examine population dynamics monoclonal populations of ab-TCR transgenic T cells or of pathogen-reactive polyclonal populations in vitro and in vivo using novel reporter mice that permit the sensitive identification, isolation and tracking of T cells on the basis of cytokine gene expression. In the previous funding period, we developed an IL-2 promoter/GFP reporter model that enabled the identification and tracking of a limited population of naive T cells in a clonal population that activates the IL-2 gene locus and those that do not. An unanticipated finding that emerged from these studies was that those T cells fated to produce effector cytokines such as IFNg in a recall response were primarily derived from a subpopulation of antigen-activated naive cells that expressed IL-2 in the primary response. Others have identified subsets of memory T cells, termed """"""""central"""""""" and """"""""effector"""""""" memory cells, which are defined by distinct patterns of chemokine receptor and selectin molecule receptor expression, and which differ in their production of either IL-2 or IFNg, respectively. Collectively, these studies support a model that places IL-2 producing central memory cells as intermediates along a pathway to effector memory cells, a model with features that are distinct from the paradigm now favored for the CDS lineage. Here we will test this model using new reporter systems that reliably permit tracking of T cells that produce IFNg or IL-2 as toolsto explore the longevity anc possible interconversion of cells defined by expression of these cytokines, as well as mechanisms that may control their survival. We will also define the relative contribution of these subpopulations for provision of B cell and CDS T cell help. We anticipate that successful completion of these studies will provide an understanding of CD4 T lineage effector and memory cell development that will suggest improved strategies for vaccine development and immunotherapy.
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