T CELL TURNOVER AND THE ROLE OF CYTOKINES

Scripps Research Institute, La Jolla CA

Investigators

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Abstract

DESCRIPTION (Adapted from the Investigator's abstract): Information will be sought on the factors controlling the turnover (rate of proliferation) and survival of memory T-cells. In normal mice, memory CD4+ and CD8+ cells have a characteristic phenotype, typified by high expression of CD44 (CD44hi). Labeling studies with DNA precursors such as bromodeoxyuridine (BrdU) have shown that the turnover of memory-phenotype T-cells in vitro is far higher than for naive-phenotype cells. The high turnover of memory-phenotype T-cells may reflect (a) continuous TCR-mediated immune responses to foreign (or self) antigens, or (b) TCR-independent "bystander" stimulation elicited by cytokines, or both. In favor of this second possibility, injecting mice with various cytokines considerably augments the turnover of memory-phenotype T-cells. Some cytokines, notably IL-15, elicit selective proliferation of CD44hi cells both in vivo and in vitro. However, other cytokines such as type I interferon (IFN-I) stimulate T-cell proliferation only in vivo and not in vitro. These and other data have led to a scenario where "inducer" cytokines such as IFN-I cause T-cell proliferation in vivo by stimulating production of "effector" cytokines (possibly IL-15) by antigen-presenting cells (APC). To assess this idea, three broad avenues of investigation are proposed. First, the possibility that IL-15 is an important effector cytokine for bystander T-cell proliferation initiated by IFN-I will be tested by using IL-15-'- or IL-15-unresponsive mice as host for normal T-cells. In addition, the capacity of IL-15 to potentiate the survival of memory T-cells will be explored. Second, a variety of different cytokines will be assessed for their capacity to act as effector cytokine inducers in vivo. Third, IFN-I and other cytokines will be tested for their ability to act as adjuvants for T-cell responses to specific antigen; the issue of whether the adjuvant function of cytokines operates at the level of APC, or T-cells or both will be explored.