The long-term goal of this project is an understanding of the mechanisms that control cell fate decisions in a clonal CD4 T cell response during the antigen-driven transition from naive to memory and effector cell specification. The experimental approach will be an examination of the population dynamics of alpha/beta-TCR transgenic T cells either in vitro, or in vivo following adoptive transfers using techniques that permit analysis of the population response at the single cell level. In the previous funding period, we developed a novel 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. Two unanticipated findings emerged from these studies. First, the effector cells that produce Thl or Th2 effector cytokines (IFNgamma/or IL-4) in a recall response are strongly linked to the subpopulation of antigen-activated naive cells that express IL-2. Second, the capacity for IL-2 gene transcription by individuals within the naive clonal T cell population appears to be restricted through a T cell intrinsic mechanism. Others have identified subsets of memory T cells defined by distinct patterns of chemokine receptor and selectin molecule receptor expression that differ in their ability to produce effector cytokines when activated ex vivo. Collectively, these studies suggest a model of T cell activation, lineage commitment and memory in which there is intrinsic """"""""immunological reserve"""""""" programmed into clonal populations of antigen-naive CD4 T cells. Here we will extend these studies using new models and methodologies for tracking clonal subpopulations stratified on the basis of naive and effector cytokine gene expression. A primary emphasis will be the examination of the lineage relationships of heterogeneous activation responses in the naive T cell response to memory and effector cell development, and the relationship of """"""""central"""""""" and """"""""effector"""""""" memory cells.
The specific aims are to test two independent, but linked, hypotheses: I. Limited complete activation of a clonal population of naive CD4 T cells reflects intrinsic heterogeneity of activation competence of individual T cells and limits memory and effector cell development. II. Effector memory T cells are terminally differentiated, short-lived cells that mediate responses in peripheral tissues, whereas central memory T cells are long-lived and are essential for maintenance of T cell memory. An understanding of the lineage relationships that control memory and effector T cell development and maintenance are of central importance for improved vaccine design to pathogens, and will contribute to improved approaches for controlling autoimmunity.
