T-cell development of TCR alpha/beta cells proceeds in the thymus along two pathways: one pathway transforms CD4-8- TCR precursor cells into mature, CD8-4+ or CD8+4- TCR hi cells via the CD8+4+ TCR lo intermediates, is very well understood. The second, a less well understood minor pathway, results in the production of mature TCR+ CD8/4- mDN cells. The mDN cells become detectable late in the ontogeny, and tend to accumulate with aging. In T-cell receptor transgenic (TCRTg) mice, thymic development is skewed towards production of TCRTg+ DN cells. This accumulation occurs at the expense of the main TCR alpha/beta lineage, and is determined by an unknown property of the TCRTg. In this application, elucidation of the developmental biology and of the functional role of TCRTg and normal mDN cells, will be sought. The hypothesis that TCRTg mDN cells are the equivalent of normal mDN cells, using IL-17 secretion, as well as trafficking, selection and gene rearrangement patterns will be tested. The mechanism of mDN cell over-production in TCR Tg mice and its dependence on the timing of expression and the affinity of the TCR transgene will be examined. Adoptive transfer experiments will focus on the function of normal and TCRTg mDN cells and their ability to alter the immune function. In light of the accumulation of these cells in aging and the possibility that they may secrete large amounts of Th2 cytokines, particular attention will be paid to their ability to influence the function of other cells during senescence, as well as on the production, expansion and homeostasis of these cells in the course of aging. In normal mice, mDN cells contain cells that secrete high levels of Th2 cytokines. It is not clear to what extent these unique cells may be responsible for the dominance of Th2 responses in aging, which is believed to contribute to the senescent immunodeficiency. Furthermore, understanding the development and function of this unique T-cell subset may also be relevant to the fields of autoimmunity and allergy.
