Post-Thymic T-Cell Functional Heterogeneity

University Of Alabama At Birmingham, Birmingham AL

Investigators

Linked publications & trials

Abstract

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