Importance of the inducible costimulator molecule for the induction of allergic immune responses and its decreased expression on T helper cells after venom immunotherapy

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Abstract
The 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-gamma. Expression of ICOS on CD4+ T cells was induced, in a dose-dependent 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.