Regulation of human lymphocyte proliferation by a heterodimeric cytokine, IL-12 (cytotoxic lymphocyte maturation factor).
IL-12 is a heterodimeric cytokine that was identified on the basis of its ability to synergize with IL-2 in the induction of cytotoxic effector cells and was originally called cytotoxic lymphocyte maturation factor (CLMF). IL-12 was also found to stimulate the proliferation of PHA-activated lymphoblasts which were greater than 90% CD3+ T cells. In this report we further characterize the effects of IL-12 on lymphocyte proliferation. Studies with purified subpopulations of PHA-activated lymphoblasts and with cloned lines of human T cells indicated that IL-12 caused the proliferation of activated T cells of both the CD4+ and CD8+ subsets. This effect of IL-12 was independent of IL-2 because it was not blocked by antibodies to either IL-2 or IL-2R. The maximum proliferation induced by IL-12 was 31 to 72% of the maximum caused by IL-2; however, IL-12 was active at a lower effective concentration (EC50 = 8.5 +/- 1.3 pM) than IL-2 (EC50 = 52 +/- 8 pM). Combination of suboptimal amounts of IL-12 and IL-2 resulted in additive proliferation, up to the maximum induced by IL-2 alone. IL-12 also caused the proliferation of lymphocytes activated by culture with IL-2 for 6 to 12 days. CD56+ NK cells were among the IL-12-responsive cells in the IL-2-activated lymphocyte population. Unlike IL-2 or IL-7, IL-12 caused little or no proliferation of resting peripheral blood mononuclear cells (PBMC). In this regard, IL-12 was similar to IL-4. However, IL-12 could enhance the proliferation of resting PBMC caused by suboptimal amounts of IL-2, whereas IL-4 inhibited IL-2-induced PBMC proliferation. Thus, IL-12 is a growth factor for activated human T cells and NK cells; however, its spectrum of lymphocyte growth-promoting properties is distinct from that of IL-2, IL-4, or IL-7.
Gately
M K
MK
Department of Immunopharmacology, Hoffmann-La Roche Inc., Nutley, NJ 07110.
Desai
B B
BB
Wolitzky
A G
AG
Quinn
P M
PM
Dwyer
C M
CM
Podlaski
F J
FJ
Familletti
P C
PC
Sinigaglia
F
F
Chizonnite
R
R
Gubler
U
U
D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology; D019002:CD56 Antigen; D016827:CD8 Antigens; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005455:Fluorescent Antibody Technique; D006801:Humans; D066298:In Vitro Techniques; D018664:Interleukin-12; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D013601:T-Lymphocytes / Q000502:physiology
D000945:Antigens, Differentiation, T-Lymphocyte; D019002:CD56 Antigen; D016827:CD8 Antigens; D007376:Interleukin-2; D015851:Interleukin-7; D007378:Interleukins; D018664:Interleukin-12; D015847:Interleukin-4