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SUMMARYDendritic cells (DC) are able to induce not only T helper 1 (Th1) but also Th2 immune responses after stimulation with allergens. While DC-derived interleukin (IL)-12 and IL-18 are the key factors for the induction of Th1 cells, early signals being involved in Th2 differentiation are less well characterized so far. To analyse such early signals we used an antigen-specific setting with CD4 þ T cells from atopic donors stimulated in the presence of autologous mature DC, which were pulsed with different allergen doses. The addition of increasing amounts of allergen during DC maturation with tumour necrosis factor-a, IL-1b and prostaglandin E 2 resulted in enhanced secretion of IL-6 and IL-12 by DC followed by increased production of Th1 (interferon-g; IFN-g) as well as Th2 (IL-4, IL-5) cytokines by CD4 þ T cells. The coculture of allergen-treated DC and CD4 þ T cells also led to a dose-dependent expression of active signal transducer and activator of transcription-6 (STAT6), which was visible already after 1 hr. Additionally, rapid phosphorylation of STAT6 was seen in immature DC after stimulation with allergens but not with lipopolysaccharide or human serum albumin. STAT6 phosphorylation was associated with the production of IL-13 by DC. The addition of neutralizing anti-IL-13 antibodies during maturation of DC inhibited STAT6 phosphorylation in CD4 þ T cells as well as the production of IL-4, and to a lesser extent of IL-5, while IFN-g production was not affected. Addition of exogenous IL-13 enhanced mainly the secretion of IL-4. Taken together, DC-derived IL-13, which is released after exposure to allergens appears to be one of the critical factors for DC to acquire the capability to induce Th2 cytokine production.

SUMMARYThe inducible costimulator (ICOS), a newly identified member of the CD28 receptor family that is induced after T-cell activation, and its ligand (ICOSL), being expressed on activated monocytes and dendritic cells play a key role in T-cell-mediated immune responses. As ICOS costimulation also seems to regulate T helper 2 effector cells, the aim of this study was to analyse the function of this molecule in allergic immune responses and their specific therapy, mainly venom immunotherapy (VIT). CD4 + T cells from grass pollen-, or bee or wasp venom-allergic donors were stimulated in the presence of autologous mature dendritic cells, which were pulsed with different allergen doses. In this system, costimulation of ICOS strongly enhanced the production of the T helper 2 cytokines interleukin (IL)-4, IL-5 and IL-10 and, to a lesser extent, secretion of the T helper 1 cytokine, interferon-c. Expression of ICOS on CD4 + T cells was induced, in a dosedependent manner, after a few days of stimulation with allergen-pulsed dendritic cells, reaching a peak on day 6. The upregulation of ICOS after stimulation with venom allergens was significantly reduced after VIT. Addition of exogenous IL-10 (which is induced during VIT) to the co-cultures before VIT also led to an inhibition of ICOS expression, while blocking of IL-10 in co-cultures after VIT partially restored the expression of ICOS. These data indicate that the inhibition of T cells after immunotherapy also involves decreased induction of the costimulatory molecule ICOS, which, in turn, seems to be dependent on the presence of IL-10, also associated with the inhibited status of T cells after VIT. This makes the ICOS-ICOSL pathway a potential target for therapeutic intervention in T helper 2-mediated diseases, such as allergic diseases.

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