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 ...

Polyclonal CD8+ T cells, with a marked innate/memory phenotype, high eomesodermin (Eomes) expression, and the capacity to generate IFN-γ rapidly without prior exposure to antigen, have been described in mice. However, even though a pool of human CD8

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Although it is generally acknowledged that cytokines regulate normal hematopoiesis in an autocrine/paracrine fashion, their possible role in chronic myelogenous leukemia (CML) and resistance to imatinib mesylate treatment remain poorly investigated. Here, we report that CD34(þ) progenitors from patients with CML at diagnosis are selectively targeted by the cytokine/alarmin interleukin (IL)-33. Indeed, CML CD34(þ) progenitors upregulate their cell surface expression of the IL-33-specific receptor chain ST2, proliferate and produce cytokines in response to IL-33, conversely to CD34(þ) cells from healthy individuals. Moreover, ST2 overexpression is normalized following imatinib mesylate therapy, whereas IL-33 counteracts in vitro imatinib mesylate-induced growth arrest in CML CD34(þ) progenitors via reactivation of the STAT5 pathway, thus supporting the notion that IL-33 may impede the antiproliferative effects of imatinib mesylate on CD34(þ) progenitors in CML. Clinically, the levels of circulating soluble ST2, commonly considered a functional signature of IL-33 signaling in vivo, correlate with disease burden. Indeed, these elevated peripheral concentrations associated with a high Sokal score predictive of therapeutic outcome are normalized in patients in molecular remission. Finally, we evidenced a facilitating effect of IL-33 on in vivo maintenance of CD34(þ) progenitors from patients with CML by using xenotransplant experiments in immunodeficient NOG mice, and we showed that engraftment of mouse BCR-ABL-transfected bone marrow progenitors was less efficient in IL-33-deficient mice compared with wild-type recipients. Taken together, our results provide evidence that IL-33/ST2 signaling may represent a novel cytokine-mediated mechanism contributing to CML progenitor growth and support a role for this pathway in CML maintenance and imatinib mesylate resistance. Cancer Res; 74(10); 2669-76. Ó2014 AACR.

The molecular status of Abs in the vaginal fluid is reconsidered as a basis for immunization strategies for women' vaccination against HIV. Analysis of separated immunoglobulins (Igs) shows a large proportion of uncleaved IgG, whereas the low amount of IgA includes SIgA, monomers and fragments. SIgM is at a very low level, while free SC molecules are abundant. In addition to the already documented local synthesis, vaginal IgG contains serum-derived tetanus antitoxins. The IgG could reach the lumen by diffusion, and/or be transported by an Fc receptor-associated mechanism as suggested by the subclass imbalance in favour of the IgG1 isotype. VAginal SIgA contains very low levels of antibodies o the cell-well carbohydrates from a dental caries-associated streptococcus confirming the participation of the secretory immune system. IN addition, the low percentage of IgA2 suggests tha a proportion of vaginal SIgA can also derive from actively transported serum polymers. In agreement with our previous studies showing induction of vaginal tetanus antitoxins by intramuscular immunization, these results are in favour of classical, parenteral vaccinations to induce protection of the human vagina.

A randomized study was conducted in 40 allogeneic marrow recipients to compare the immunogenicity of two Haemophilus influenzae type b (Hib) vaccines (either the Hib capsular polysaccharide [Hib-CPS] or tetanus toxoid-conjugated Hib-CPS [Hib-CPS-T]). A second injection consisted of Hib-CPS-T. Before immunization, 3 patients had serum antibody levels > 1 microgram/mL. After the first injection, the response was better after Hib-CPS-T than after Hib-CPS but lower than in normal subjects; a number of patients lacked any IgG antibody response, especially after Hib-CPS. Of patients who received two injections of Hib-CPS-T, 85% achieved an antibody concentration > or = 1 microgram/mL. Hib-CPS-T induced a response in IgG2-deficient patients whereas Hib-CPS alone did not. IgG antibodies predominantly belonged to the IgG1 subclass. The antibody response was better in patients immunized late after graft. This study shows that Hib-CPS-T is more immunogenic than Hib-CPS in marrow recipients.

The endogenous molecules high mobility group box 1 (HMGB1) and interleukin-33 (IL-33) have been identified as alarmins, capable of mediating danger signals during tissue damage. Here, we address their possible role as innate-immune mediators in ischemia-reperfusion injury (IRI) following human kidney transplantation. We analysed serum and urinary HMGB1 and IL-33 levels, all determined by enzyme-linked immunosorbent assay, in a cohort of 26 deceased renal transplant recipients. Urinary HMGB1 and IL-33 levels were significantly increased as soon as 30 min after reperfusion, as compared to those before treatment. Moreover, both serum and urinary IL-33 (but not HMGB1) increase was positively correlated with cold ischemia time, from 30 min to 3 days post-transplantation. In vitro, human umbilical vein endothelial cells subjected to hypoxia conditions released both HMGB-1 and IL-33, while only the latter was further increased upon subsequent re-oxygenation. Finally, we postulate that leukocytes from renal recipient patients are targeted by both HMGB1 and IL-33, as suggested by increased transcription of their respective receptors (TLR2/4 and ST2L) shortly after transplantation. Consistent with this view, we found that iNKT cells, an innate-like T cell subset involved in IRI and targeted by IL-33 but not by HMGB1 was activated 1 hour post-transplantation. Altogether, these results are in keeping with a potential role of IL-33 as an innate-immune mediator during kidney IRI in humans.

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