In vitro maturation of human neonatal CD4 T lymphocytes. I. Induction of IL-4-producing cells after long-term culture in the presence of IL-4 plus either IL-2 or IL-12

Abstract

Recent studies in the mouse have established that IL-4 and IL-12 direct the development of Ag-stimulated naive CD4 T cells into, respectively, type 2 and type 1 Th cells. We report that prolonged exposure of immunologically naive and unstimulated human neonatal CD4 T cells to IL-4 or to IL-4 plus either IL-2 or IL-12 markedly affects their cytokine production on primary stimulation with PMA and ionomycin. IL-4 induces long-term proliferation of neonatal T cells and after 3 wk of culture these are capable of producing high levels of Th1 (IL-2, IFN-gamma) but no Th2 (IL-4, IL-5) cytokines; IL-4-primed cells are homogenously CD45RO-/RA+ and CD31+. After culture in the presence of IL-4 + IL-2 or IL-4 + IL-12, neonatal T cells are enriched in CD45RO+ and CD31- cells and they can produce Th2 as well as Th1 cytokines. In response to primary stimulation with PMA and ionomycin, cells primed with IL-4 + IL-2 produce IL-4, IL-5, and IL-10 and the same levels of IL-2 and IFN-gamma as IL-4-primed cells. Cells primed with IL-4 + IL-12 produce very high levels of both IL-4 and IFN-gamma but no IL-5. Endogenous IFN-gamma that is detected in primary cultures containing IL-4 + IL-12 does not inhibit, but rather enhances, the ability of the cells to produce IL-4. Further analysis of IL-4 + IL-12-primed cells reveals that IL-4 is mainly produced by CD31- cells and that these cells can trigger B cells to synthesize Ig including IgE. Finally, positively selected CD31+ cells remain CD31+ and are poor IL-4 producers after 3 wk of culture with IL-4 + IL-12, suggesting that these two cytokines promote the selective expansion of the small number of CD31- cells that are present in freshly isolated neonatal CD4 T cells.