Understanding how memory develops in the immune system is an important issue in basic science and in clinical medicine, both in terms of promoting an immune response and, conversely, in blocking the pathway that leads to an overactive state (allergy, autoimmunity). However, the mechanisms underlying the generation of memory lymphocytes are poorly understood. This proposal is aimed at answering the important question of whether the generation of memory T cells is associated with a stable alteration of cytokine expression. We focus here on the generation of mouse CD4+ memory T cells that help B cell antibody responses (memory helper T cells) in relation to attainment of the capacity to secrete IL- 4. We wish to distinguish whether there are pre-existing CD4+ subsets committed to this IL-4 potential, or instead whether such subsets are generated de novo by a maturation process following antigenic stimulation. We will examine TCR-V gene usage of CD4+ subsets by establishing T hybrids from a 2B4 TCR Vbeta (or Valpha) transgenic mouse to determine whether the cell subsets capable of rapid IL-4 secretion (""""""""IL-4+"""""""") show restricted TCR V-gene usage, evidence for antigenic selection. Then we will attempt a direct demonstration of IL-4- naive cell transition to IL-4+ cells at the single cell level. Finally, we will examine whether memory T helper cells are already committed to a specific cytokine potential or not. If we can demonstrate that IL-4+ cells are produced during the process of memory T cell generation, then this provides an important concept of lymphocyte maturation; that is, specialization of effector function similar to memory B cell generation characterized by immunoglobulin isotype switch. These studies will provide greater understanding of the generation and function of memory cells in the immune system, both in normal and diseased states.
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