IL-33 has recently been identified as a cytokine endowed with pro-Th2 functions, raising the question of its effect on invariant natural killer T cell (iNKT), which are potent IL-4 producers. Here, we report a two-fold increase of iNKT-cell counts in spleen and liver after a 7-day treatment of mice with IL-33, which results from a direct effect, given that purified iNKT cells express the T1/ST2 receptor constitutively and respond to IL-33 by in vitro expansion and functional activation. Conversely to the expected pro-Th2 effect, IL-33 induced a preferential increase in IFN-c rather than IL-4 production upon TCR engagement that depended on endogenous IL-12. Moreover, in combination with the pro-inflammatory cytokine IL-12, IL-33 enhanced IFN-c production by both iNKT and NK cells. Taken together these data support the conclusion that IL-33 can contribute as a co-stimulatory factor to innate cellular immune responses.Key words: Cytokines . Inflammation . Natural killer cells . Natural killer T cells .Th1/Th2 cells Introduction IL-33 (or IL-1F11) has recently been identified as a ligand of the orphan T1/ST2 receptor, a member of the IL-1 receptor (IL-1R) family [1] that was initially described as a nuclear factor, nuclear factor from high endothelial venules, abundantly expressed by endothelial cells in lymphoid tissues [2,3]. IL-33 induces its biological effects through a heterodimeric complex comprising the T1/ST2 receptor [1] and the IL-1R accessory protein (IL-1RAcP), another member of IL-1R family [4,5]. T1/ST2 engagement triggers a signalling pathway that requires MyD88 and NF-kB [1,4,6]. It has long been known that T1/ST2 is expressed primarily in mast and Th2 cells and is associated with important Th2 effector functions [7][8][9]. Accordingly, IL-33 has been found to promote Th2 cytokine production by mast cells and polarized T cells in vitro, and to induce pulmonary and mucosal Th2 inflammation when administered in vivo [1].iNKT cells constitute a distinctive subpopulation of mature ab-T cells bearing an invariant TCR a-chain together with NK-cell receptors [10,11]. They recognize glycosphingolipid Ags presented by CD1d, a non-classical class I-like Ag-presenting molecule, and respond rapidly to TCR stimulation with a-galactosylceramide (a-GC) by generating a number of cytokines,
1046particularly 11]. In most disease models in which iNKT cells have been implicated their beneficial or detrimental effects have been ascribed to either Th1 or Th2 cytokines [10,11]. It has also been established that the balance between these two profiles depends essentially on the microenvironment, which favours IL-4 or IFN-g production [12][13][14][15][16][17].Given its previously established pro-Th2 functions, IL-33 seemed a plausible candidate for the regulation of iNKT-cell activities, prompting us to investigate whether it could directly interact with this regulatory cell subset to drive IL-4 production. Starting from the observation that the incidence of iNKT cells was increased in spleen and liver of mice injected with ...
