Restricted production of interleukin 4 by activated human T cells.

Abstract

Interleukin 4 (IL-4) is secreted by activated T cells and pleiotropically modulates both B-and T-lymphocyte function. In murine helper (CD4+) T-cell clones IL-4 production appears to be regulated independently of interferon Y and interleukin 2. To determine whether production of these lymphokines is also differentially regulated in uncloned human T cells, we studied lymphokine production *iy normal human peripheral T cells and T-cell subsets after ii vitro polyclonal activation. After maximal induction of lymphokine expression, IL-4 mRNA was detectable in <5% of CD41 and 1-2% of unfractionated T cells, whereas '33% and 60% of CD4' cells expressed detectable mRNA for interferon y and interleukin 2, respectively. This finding correlated with dramatically lower production of IL-4 mRNA and protein than of interferon rand interleukin 2 by peripheral blood and tonsillar T cells. The helper-inducer (CD4' CD45R-) T-cell subset, which significantly enhances in vitro immunoglobulin production, accounted for the preponderance of IL-4 mRNA accumulation and protein production by CD41 T cells; nevertheless, cells with detectable IL-4 mRNA constituted <10% of the CD4' CD45R-subset. Limitation of IL-4 production to a comparatively small population of normal human T cells could selectively regulate the effects of this lymphokine in T-cell-mediated immune responses; such selective regulation may be a fundamental mechanism for restricting the potentially pleiotropic effects of certain tymphokines to appropriate responder cells.Interleukin 4 (IL-4) is a T-cell lymphokine that modulates lymphocyte function by promoting B-cell growth, regulating immunoglobulin isotype expression, and promoting T-cell growth and cytotoxicity (1)(2)(3)(4). Interferon y (IFN-'y) (5,6) and, to a lesser extent, interleukin 2 (IL-2) (6, 7), which are primarily produced by activated T cells, also have pleiotropic effects on lymphoid cells. In certain cases all three lymphokines may have similar or synergistic activities, such as the enhancement of T-cell-mediated cytotoxicity (4,8), whereas in other situations, such as the regulation of immunoglobulin isotype expression by IL-4 and IFN-y, differential or antagonistic effects have been demonstrated (2, 9, 10).These in vitro findings raise the question as to how lymphokine production by activated T cells is regulated in vivo to result in an integrated effective immune response. One mechanism to facilitate distinct T-cell effector functions would be to limit the production of a lymphokine to a particular subtype ofT cells. Such segregation ofCD4' T-cell lymphokine production has been proposed by Mosmann and co-workers (11, 12) from the observation that most murine CD4' clones produce either IL-4 or IFN-y and IL-2 in a mutually exclusive fashion. However, most human CD4' T-cell clones do not appear to conform to this pattern (9, 13), and there is evidence that the patterns of lymphokine production obtained in clones may be influenced by the conditions used during the cloning process (14). In addition, c...

Cutting Edge: Polymorphisms in the ICOS Promoter Region Are Associated with Allergic Sensitization and Th2 Cytokine Production

“…The increase in Th2 cytokines in our system is likely attributable to secretion by memory T cells, because several groups have shown that it is predominantly memory, not naive, human T cells that produce IL-4 mRNA and protein at early time points (27). Because we also found increased levels of ICOS expression on Ϫ1413AA CD4 ϩ and CD8 ϩ T cells before activation, it is probable that increased ICOS expression is associated with an increased Th2 memory pool.…”

Human tumour-associated NK cells secrete increased amounts of interferon-γ and interleukin-4

“…However, without the application of either a variant of the RHPA called the 'sequential' RHPA, to visualise the secretion of both these cytokines by the same cells (Neill et al, 1987), or their dual labelling by immunofluorescence (Anderson et al, 1990), it is not possible to say whether the 1% of CD16+ cells which were seen to secrete IL-4 also secreted IFN-y. The possibility (Lewis et al, 1988;Anderson et al, 1990 (Chong et al, 1989). The medium transfer experiments conducted in the present study also indicate that factors secreted by tumour cells in culture, may be involved in the activation of NK cell secretory activity by the microenvironment of the tumour.…”

Interleukin 4 expressed in situ selectively alters thymocyte development.

“…RNA was quantitated spectrophotometrically, electrophoresed in 1% agarose gels made in 2.2 M formaldehyde, and blotted as previously described (29) . Hybridization and washing conditions were those previously described for 12 p-labeled DNA probes (30) . The murine 11,4 probe, which consisted of a 0.6-kb BamHI-SspI cDNA fragment (22), was "P-labeled using the random hexamer priming method (31) .…”