Interleukin-12 primes human CD4 and CD8 T cell clones for high production of both interferon-gamma and interleukin-10.
Interleukin-12 (IL-12) induces differentiation of T helper 1 (Th1) cells, primarily through its ability to prime T cells for high interferon-gamma (IFN-gamma) production. We now report that the presence of IL-12 during the first several days of in vitro clonal expansion in limiting dilution cultures of polyclonally stimulated human peripheral blood CD4+ and CD8+ T cells also induces stable priming for high IL-10 production. This effect was demonstrated with T cells from both healthy donors and HIV+ patients. Priming for IL-4 production, which requires IL-4, was maximum in cultures containing both IL-12 and IL-4. IL-4 modestly inhibited the IL-12-induced priming for IFN-gamma, but almost completely suppressed the priming for IL-10 production. A proportion of the clones generated from memory CD45RO+ cells, but not those generated from naive CD45RO- CD4+ T cells, produced some combinations of IFN-gamma, IL-10, and IL-4 even in the absence of IL-12 and IL-4, suggesting in vivo cytokine priming; virtually all CD4+ clones generated from either CD45RO(-) or (+) cells, however, produced high levels of both IFN-gamma and IL-10 when IL-12 was present during expansion. These results indicate that each Th1-type (IFN-gamma) and Th2-type (IL-4 and IL-10) cytokine gene is independently regulated in human T cells and that the dichotomy between T cells with the cytokine production pattern of Th1 and Th2 cells is not due to a direct differentiation-inducing effect of immunoregulatory cytokines, but rather to secondary selective mechanisms. Particular combinations of cytokines induce a predominant generation of T cell clones with anomalous patterns of cytokine production (e.g., IFN-gamma and IL-4 or IFN-gamma and IL-10) that can also be found in a proportion of fresh peripheral blood T cells with "memory" phenotype or clones generated from them and that may identify novel Th subsets with immunoregulatory functions.
Gerosa
F
F
Immunology and Infectious Disease Institute, University of Verona, Italy.
Paganin
C
C
Peritt
D
D
Paiola
F
F
Scupoli
M T
MT
Aste-Amezaga
M
M
Frank
I
I
Trinchieri
G
G
D015703:Antigens, CD / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002454:Cell Differentiation; D002999:Clone Cells; D006679:HIV Seropositivity / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000096:biosynthesis; D017493:Leukocyte Common Antigens; D011994:Recombinant Proteins / Q000494:pharmacology; D012016:Reference Values; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
D015703:Antigens, CD; D011994:Recombinant Proteins; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens