Although this observation is still solid, IL-4-independent pathways have recently been identified,

with cytokines such as IL-25, IL-33 and thymic stromal lymphopoietin (TSLP) added to the list of Th2-promoting factors. Nevertheless, IL-4 remains on top of the pile as a dominant Th2-promoting molecule. Interleukin-4 receptor α and the common gamma chain provide the necessary buy DMXAA type I IL-4 receptor for IL-4 binding. Signalling is transduced by the transcription factor STAT-6, which in combination with TCR-derived signals and other transcription factors, activates GATA3. These signals trigger transcription of il4 and other Th2-associated cytokines within the il4 locus, including il5 and il13. In addition, IL-2 produced as a result of TCR triggering leads to STAT-5-induced IL-4 production.48 GATA3 is both necessary and sufficient for Th2 development and lies at the heart of Th2 cell differentiation and proliferation. Transgenic over-expression of gata3 induces il449

whereas its absence abolishes il4 transcription.7,50 GATA3 also serves to stabilize chromatin rearrangement within the il4 locus during Th2 differentiation and represses IL-12-mediated STAT4 expression and Th1 development (A more detailed review of the il4 locus and GATA3 can be found in refs 51,52). Based upon in vitro observations with IL-4, it stood to reason that in vivo IL-4 would be the signal necessary for Th2 differentiation. The precise source of early IL-4 in vivo eluded immunologists for a long Selleck PD98059 time with innate cells such as

natural killer T cells initially proposed.53 Despite observations made approximately 20 years ago that basophils can produce IL-4 and are present in lymphoid organs54 a flurry of recent papers re-invigorated the basophil and identified the influx of IL-4gfp+ basophils into lymph nodes following infection with Nippostrongylus brasiliensis23,55 or Schistosoma mansoni19 or immunization with papain.17 However, reiterated throughout this review is the idea that in vitro observations provide likely, but not guaranteed, hypotheses for in vivo scenarios. Interleukin-4 is the perfect example of in vitro dependence and in vivo redundancy. Lck Th2 cells can differentiate in vivo in the complete absence of IL-4. Normal in vivo Th2 responses were observed in IL-4- and STAT6-deficient mice infected with N. brasiliensis suggesting that Th2 cells can differentiate independent of IL-4–STAT-6 signalling.10,56 Of note, GATA3 appears to be essential for in vitro and in vivo generation of Th2 cells.50 If Th2 responses can develop in the absence of IL-4, IL-4Rα and STAT-6, then which cytokine signals compensate in the absence of this pathway? Several candidates have been identified. Firstly, TSLP, a cytokine produced by a variety of cells including epithelial cells,57 mast cells,58 DCs59 and basophils,17,60 can be induced by Toll-like receptor 3 (TLR3), IL-4 or IL-13 signalling.