Cell division is not a "clock" measuring acquisition of competence to produce IFN-gamma or IL-4.
Naive CD4 T cells acquire the potential to produce IFN-gamma and IL-4 by culture in the presence of their cognate Ag, APC, and appropriate cytokines. In this study, we show that commitment to IFN-gamma production on the part of rigorously purified naive CD4 T cells can occur without cell division. Indeed, even entry into S phase is not essential. Moreover, both CD4 and CD4/CD8 thymocytes from TCR-transgenic mice (5CC7 mice) on a Rag2(-/-) background can acquire IFN-gamma-producing capacity when stimulated by peptide, APC, and IL-12. These cells can do so without dividing and some acquire IFN-gamma-producing activity without entry into S phase. Not only is cell division not required for acquisition of cytokine-producing potential, cell populations that have undergone the same numbers of divisions can have quite different proportions of IFN-gamma- or IL-4-producing cells, depending on the duration of priming or, in the case of IL-4, on the concentration of peptide. Thus, cell division is not a clock for the expression of these cytokines. Factors associated with priming conditions including strength of stimulation, duration of priming, and number of divisions each play a role.
Ben-Sasson
S Z
SZ
Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Gerstel
R
R
Hu-Li
J
J
Paul
W E
WE
D000818:Animals; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004261:DNA Replication / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D005260:Female; D007114:Immunization; D007371:Interferon-gamma / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000096:biosynthesis*; D007399:Interphase / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D018655:Lymphocyte Count; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013950:Thymus Gland / Q000166:cytology; D019895:Transposases / Q000172:deficiency / Q000235:genetics
D000941:Antigens; D016207:Cytokines; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D015847:Interleukin-4; D007371:Interferon-gamma; D019895:Transposases