What is not clear is the influence of the different IL-4-producing cells within the lymph node. Do basophils secrete IL-4 multi-directionally and T cells secrete focused IL-4? If IL-4 secretion is representative of other effector cytokine secretions, the former study129 supports the notion that cytokines are only secreted at the site of antigen re-encounter,

spatially separating differentiation from effector function. Whether peptide–MHC complexes are the final or only trigger activating effector Th2 cells in non-lymphoid tissue or if signals with or without TCR engagement can trigger effector function is not clear. The local cytokine environment, including IL-3384 and TSLP,130 can enhance Th2 cytokine secretion, but whether ST2 and TSLP-R ligation also requires TCR engagement is not clear. Furthermore, GDC-0068 supplier the cross-talk between damaged stroma following invasion, tissue damage, or danger signals and their direct impact on selleck Th2 cells has not been reported. The impact and role of Th2-derived cytokines has been widely reported. It is undisputable that IL-4 is required for optimal IgG1 and IgE class switching in B cells,131 alternative activation of macrophages132 and Th2 stability; IL-5 mobilizes, matures133 and recruits eosinophils134 and IL-13 induces goblet cell differentiation, mucus secretion and tissue repair.135 Th2 cells

can certainly provide this trio of potent cytokines, but they are not the only ones. The recently reported type-2 innate-like

cells seem more than capable of fulfilling this role Fenbendazole as cytokine providers but they do not appear to be controlled by antigen specificity. In addition to overlapping cues for the development of Th2 cells, their functional properties may also have overlap and redundancy. For example, infection of IL-5, IL-9 and IL-13 compound cytokine-deficient mice with N. brasiliensis demonstrated the ability of IL-4 to mediate worm expulsion,136 although these mice have not been extensively studied. Nevertheless, intestinal helminth infection models have unanimously identified mechanisms of protection optimally mediated by αβ+ CD4+ Th2 cells activating a suite of innate cells. The inflammatory phenotype seen in Th2-driven asthma is also characterized by the release of IL-4, IL-5, IL-13 and IL-9.137 These features of disease have focused researchers for many years on developing strategies to perturb Th2 development and effector function to benefit allergies and to identify ways of enhancing Th2 functions to protect against helminths, or at least, the intestinal-dwelling helminths. Therapeutic approaches that involve the use of biological modifiers such as monoclonal antibodies that target Th2-associated cytokines are being tested (reviewed in ref. 138). Interestingly, such intervention studies have shown that selective inhibition of IL-4 is not effective for the treatment of asthma.