IMPAIRED SURVIVAL AND PROLIFERATION IN IL-7 RECEPTOR-DEFICIENT PERIPHERAL T-CELLS

Mice genetically deficient in IL-7R alpha are highly lymphopenic in th e peripheral lymphoid organs, The functional competence of T cells tha t have developed in the absence of an IL-7R signal was investigated, T hree important observations were made using several in vitro activatio n regimens. First, stimulation of T cells from IL-7R -/- mice at limit ing dilution with immobilized Abs to CD3, CD4 or CD8, and CD18 reveale d a six- to sevenfold reduction in the frequency of clonogenic T cells compared with T cells from IL-7R +/+ mice, IL-7R -/- T cells were als o significantly less responsive to alloantigen as well as to receptor- independent stimuli such as PMA and ionomycin, Furthermore, the averag e clone size of single IL-7R -/- T cells was 50% smaller than that of IL-7R +/+ T cells. These data suggest that the reduced clonogenicity w as predominantly due to intrinsic deficiencies in the ability of IL-7R -/- T cells to proliferate upon stimulation, Second, analysis of the kinetics of cell growth of IL-7R -/- T cells revealed that a significa nt proportion of T cells failed to proliferate within the first 72 h o f in vitro stimulation, with the majority undergoing programmed cell d eath. Third, both clonogenic IL-7 -/- T cells and IL-7R +/+ T cells sh owed a similar proliferative response in the presence of IL-2 and simi lar survival kinetics, indicating that a subpopulation of IL-7R -/- T cells is functionally mature. We propose that an absence of IL-7R sign aling not only affects T cell development in the thymus, but also resu lts in the accumulation of functionally inactive T cells in the periph ery.