Distinct regulatory effects of IL-4 and TNF-alpha during CD3-dependent and CD3-independent initiation of human T-cell activation.
The present study examines the effects of IL-4 and TNF-alpha on the CD3-dependent (Ag/MHC-initiated or anti-CD3 mAb-initiated) and CD3-independent (IL-2-initiated) pathways of the initiation of human T-cell activation. Both IL-4 and TNF-alpha significantly augmented the CD3-dependent T-cell proliferation induced by either irradiated OKT3 hybridoma cells or allogeneic B cells. In contrast, the CD3-independent IL-2-initiated T-cell proliferation was enhanced by TNF-alpha and significantly inhibited by IL-4. Although the growth-enhancing effects of both IL-4 and TNF-alpha on the CD3-dependent T-cell proliferation were noticeable regardless of when these cytokines were introduced in culture, the inhibitory effect of IL-4 on the CD3-independent IL-2-initiated T-cell activation was observed only if IL-4 was added at the initiation but not later than 24 hr of "T cells + IL-2" cultures. The growth-enhancing effects of both IL-4 and TNF-alpha on the CD3-dependent T-cell activation were not confined to any one subset of T cells. On the other hand, IL-4 inhibited the IL-2-induced proliferation of CD4+ (helper/inducer) T cells and CD45R+ (virgin) T cells but not that of CD8+ (cytotoxic/suppressor) T cells and CD45R (memory) T cells. When examined for their effects on cytokine production, CD3-dependent production of IL-2 and IFN-gamma was affected by neither cytokine, whereas IL-4 strongly inhibited the production of IFN-gamma by IL-2-stimulated T cells. Consistent with their enhancing and inhibitory effects, respectively, on IL-2-induced T-cell proliferation, TNF-alpha augmented and IL-4 inhibited the development of IL-2-stimulated MHC-unrestricted cytolytic (MUC) T-cell activity directed against tumor cells. When deprived of IL-2, MUC T cells rapidly lose their cytolytic activity, and despite its inhibitory effect on the development of MUC T cells, exposure of IL-2-deprived MUC T cells with decaying cytolytic activity to IL-4 retards the decay in their cytolytic activity. These results suggest the differential regulatory effects of IL-4 and TNF-alpha during human T-cell activation.
Damle
N K
NK
Department of Clinical Biology, CETUS Corporation, Emeryville, CA 94608.
Doyle
L V
LV
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology*; D017252:CD3 Complex; D002457:Cell Extracts / Q000502:physiology*; D003601:Cytotoxicity Tests, Immunologic; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis; D007376:Interleukin-2 / Q000032:analysis; D015847:Interleukin-4; D007378:Interleukins / Q000502:physiology*; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*; D014020:Tissue Extracts / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D002457:Cell Extracts; D007376:Interleukin-2; D007378:Interleukins; D011948:Receptors, Antigen, T-Cell; D014020:Tissue Extracts; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma