Stimulation of murine CD4+ T cells with staphylococcal enterotoxin B (SEB) results in the preferential development of T helper (Th) 1 cells [i.e. high interferon (IFN)-gamma and low interleukin (IL)-4, IL-5 and IL-10]; whereas in response to plate-bound anti-CD3 or anti-T cell receptor-alpha beta, Th1 as well as Th2 cells develop. In the present study, we examined the mechanism which is responsible for the selective Th1 development in the SEB system. The addition of IL-4 resulted in a strong development of Th2 cells showing that SEB stimulation can result in Th2 differentiation. Co-stimulation with anti-CD28 was insufficient in this regard. Lack of Th2 development in the SEB system was in part due to the inhibitory effect of endogenously produced transforming growth factor-beta (TGF-beta), because anti-TGF-beta allowed the development of Th2 cells. Similarly, TGF-beta inhibited Th2 development and stimulated Th1 development in the anti-CD3 system. This shift was only partially prevented by also including IL-4 in the cultures. The effects of TGF-beta could only partially be explained by stimulation of IFN-gamma or inhibition of IL-4 as intermediatory cytokines: (1) TGF-beta stimulated Th1 development even in the presence of anti-IL-4 and anti-IFN-gamma, and (2) a strong inhibitory effect of anti-TGF-beta on Th1 development was still observed when anti-IL-4 and IFN-gamma were simultaneously added to the cultures. It is concluded that SEB favors Th1 development by stimulation of TGF-beta production. Inhibition of Th2 development by TGF-beta is due, in part, to inhibition of IL-4 and stimulation of IFN-gamma, and, in part, to a direct effect of TGF-beta on the responding T cells.
Aging is accompanied by an increased fraction of memory CD4+ T cells. Despite the fact that human memory cells have been reported to produce high levels of IL-2, studies in mice and man indicate an age-related decline in IL-2 production. In the present study, we examined whether these conflicting results depend on the activation pathway employed in a comparison of phenotypically distinct CD4+ T cells from young and aged mice. Our data indicate an age-related decline in IL-2 production by CD4+ T cells when the cells were stimulated with concanavalin A in the presence of accessory cells or the combination of immobilized anti-CD3 and soluble anti-CD28. However, when CD4+ T cells were only stimulated with immobilized anti-CD3, an age-related increase in IL-2 production was observed. This age-related increase in IL-2 could be attributed to the ability of CD4+ T cells from aged mice to produce IL-4 on this stimulation, since anti-IL-4 inhibited the IL-2 production in these cultures to levels found with cells from young mice. The addition of exogenous IL-4 greatly enhanced the IL-2 production of CD4+ T cells from young mice to levels far beyond that of the aged counterparts, emphasizing the dominant role of IL-4 in the induction of IL-2 stimulated with immobilized anti-CD3. No differences were observed in the activation requirements of Mel14- CD4+ T cells from young and aged mice.(ABSTRACT TRUNCATED AT 250 WORDS)
CD4+ T cell clones have been demonstrated to display a differential sensitivity for the induction of cAMP. In the present study we investigated whether the differential sensitivity of CD4+ T cell clones for cAMP inducers is also applicable to freshly isolated phenotypically and functionally distinct CD4+ T cell subsets that develop naturally in aging mice. Our results show that the concanavalin A induced and anti-CD3 induced proliferative response of CD4+ T cells from young mice is more sensitive for prostaglandin E2 (PGE2) and forskolin than that of their aged counterparts, although the IL-2 production by these cells was equally sensitive. In contrast, only a slight or no inhibitory effect of these cAMP inducers was found when the cells were stimulated with the combination of phorbol myristate acetate and ionomycin. In contrast to the findings obtained with Th2 clones, IL-4 production by freshly isolated CD4+ T cells was inhibited by the cAMP inducers, whereas exogenous IL-2 had no restorative effect. However, the IL-4 production by CD4+ T cells from aged mice was less sensitive than the IL-4 production by CD4+ T cells from young mice, although CD4+ T cells from aged mice showed significantly higher levels of intracellular cAMP in response to PGE2. These higher levels of cAMP were related to the increased fraction of memory cells in aged mice: the Mel-14- Pgp-1++ CD4+ T cells responded with at least 2-fold higher levels of intracellular cAMP than the naive cells in young as well as in aged mice. Although memory CD4+ T cells from young as well as aged mice responded vigorously to PGE2 by an enhancement of intracellular cAMP, only the IL-4 production by cells from young mice was significantly inhibited. Therefore, it is not likely that the induction of cAMP is a major event in the skewing of a primary response towards a Th2 type of response.
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