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.
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.
Wu
C Y
CY
University of Montreal, Notre-Dame Hospital Research Center, Canada.
Demeure
C E
CE
Gately
M
M
Podlaski
F
F
Yssel
H
H
Kiniwa
M
M
Delespesse
G
G
D000328:Adult; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D002478:Cells, Cultured; D006801:Humans; D016130:Immunophenotyping; D066298:In Vitro Techniques; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000032:analysis; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology*; D013997:Time Factors
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D007376:Interleukin-2; D007378:Interleukins; D008562:Membrane Glycoproteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma