IL-12 induces the production of IFN-gamma by neonatal human CD4 T cells.
A major difference between "naive" and "memory" or "effector" Th cells is the spectrum of cytokines that they are capable of producing. After stimulation naive cells produce only IL-2, whereas memory cells produce several cytokines including IFN-gamma and IL-4. Using umbilical cord blood-derived CD4 T cells as a source of naive T cells, we first report that these cells are capable of producing large amounts of IFN-gamma when cultured with low concentrations of IL-12. The response is time- and dose-dependent, and it is observed at the protein and mRNA levels. IL-12 also induces neonatal CD4 T cells to produce lymphotoxin but not IL-2, TNF-alpha, or IL-4. The production of IFN-gamma by IL-12-stimulated neonatal T cells is associated with a small but significant T cell activation evidenced by DNA synthesis and by the expression of the activation markers CD25, CD71, and HLA-DR; moreover, it is inhibited by hydrocortisone, cyclosporin A, and transforming growth factor-beta. The response to IL-12 is enhanced and is much more rapid when CD4 T cells are cultured in the presence of accessory cells or of exogenous IL-1, IL-2, or TNF-alpha. Using a three-step culture system, we next show that IL-12 induces the maturation of resting naive CD4 T cells into cells producing both IL-2 and IFN-gamma but not IL-4 upon stimulation with PMA and ionomycin. Endogenously produced IFN-gamma plays a role in this IL-12-induced T cell maturation, as shown by the inhibitory effect of neutralizing IFN-gamma antibodies. Finally, we show that IL-12 supports the production of IFN-gamma during primary stimulation of neonatal T cells via the CD3/TCR complex by means of either immobilized anti-CD3 mAb or superantigen-coated (Staphylococcus enterotoxin B) fixed L cell transfectants expressing HLA-DR. It is suggested that IL-12 is involved in the selection of Th1 type immune responses.
Wu
C Y
CY
Notre-Dame Hospital Research Center, University of Montreal, Canada.
Demeure
C
C
Kiniwa
M
M
Gately
M
M
Delespesse
G
G
D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects; D005312:Fetal Blood; D006801:Humans; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12; D007376:Interleukin-2 / Q000378:metabolism; D007378:Interleukins / Q000494:pharmacology*; D015759:Ionomycin / Q000494:pharmacology; D017493:Leukocyte Common Antigens / Q000032:analysis; D008213:Lymphocyte Activation / Q000187:drug effects; D010703:Phorbol Esters / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology
D007376:Interleukin-2; D007378:Interleukins; D010703:Phorbol Esters; D018664:Interleukin-12; D015759:Ionomycin; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens