Type 2 immunity is a stereotyped host response to allergens and parasitic helminths that is sustained in large part by the cytokines IL-4 and IL-13. Recent advances have called attention to the contributions by innate cells in initiating adaptive immunity, including a novel lineage-negative population of cells that secretes IL-13 and IL-5 in response to the epithelial cytokines IL-25 and IL-33. Here, we use IL-4 and IL-13 reporter mice to track lineage-negative innate cells that arise during type 2 immunity or in response to IL-25 and IL-33 in vivo. Unexpectedly, lineage-negative IL-25 (and IL-33) responsive cells are widely distributed in tissues of the mouse and are particularly prevalent in mesenteric lymph nodes, spleen, and liver. These cells expand robustly in response to exogenous IL-25 or IL-33 and after infection with the helminth Nippostrongylus brasiliensis, and they are the major innate IL-13-expressing cells under these conditions. Activation of these cells using IL-25 is sufficient for worm clearance, even in the absence of adaptive immunity. Widely dispersed innate type 2 helper cells, which we designate Ih2 cells, play an integral role in type 2 immune responses.T ype 2 immune responses are important for the control of infections at mucosal barriers and the development of allergic inflammation. These responses are characterized by eosinophilia, elevated IgE, goblet cell metaplasia with enhanced mucus production, and smooth muscle hyperreactivity, all of which rely critically on production of the canonical type 2-associated cytokines IL-4, IL-5, and IL-13 (1, 2). Although adaptive Th2 cells and follicular T cells are important sources of these cytokines (3), various innate cells, including eosinophils, basophils, and mast cells, have also been implicated as producers of these cytokines in various model systems (1, 2, 4, 5). More recently, the cytokines IL-25 and IL-33, members of the IL-17 and IL-1 cytokine families, respectively, were found to induce type 2 cytokine production when administered to mice, implicating these cytokines in the initiation of type 2 immune responses (6, 7). IL-25 and IL-33 are expressed by epithelial cells, macrophages, and possibly other cell types (8), and they are expressed at elevated levels during infection with parasitic helminths (9, 10) or after challenge with allergens (9, 11). Administration of exogenous IL-25 or IL-33 to mice leads to markedly enhanced levels of IL-4, IL-5, and IL-13 and many of the tissue features of a type 2 immune response (6, 7). Conversely, deficiency in IL-25 leads to diminished IL-4, IL-5, and IL-13 production and variable delays in worm clearance in different helminth models (12, 13). Similarly, mice unable to respond to IL-33 because of deficiency in the T1-ST2 subunit of the IL-33 receptor display diminished Th2-associated cytokines and decreased granuloma formation after injection of Schistosoma mansoni eggs (14).Some of the original descriptions of these cytokines as well as more recent reports have noted the capacity of exogenous ...

T-bet is a member of the T-box family of transcription factors that appears to regulate lineage commitment in CD4 T helper (TH) lymphocytes in part by activating the hallmark TH1 cytokine, interferon-gamma (IFN-gamma). IFN-gamma is also produced by natural killer (NK) cells and most prominently by CD8 cytotoxic T cells, and is vital for the control of microbial pathogens. Although T-bet is expressed in all these cell types, it is required for control of IFN-gamma production in CD4 and NK cells, but not in CD8 cells. This difference is also apparent in the function of these cell subsets. Thus, the regulation of a single cytokine, IFN-gamma, is controlled by distinct transcriptional mechanisms within the T cell lineage.

The T helper lymphocyte is responsible for orchestrating the appropriate immune response to a wide variety of pathogens. The recognition of the polarized T helper cell subsets Th1 and Th2 has led to an understanding of the role of these cells in coordinating a variety of immune responses, both in responses to pathogens and in autoimmune and allergic disease. Here, we discuss the mechanisms that control lineage commitment to the Th1 phenotype. What has recently emerged is a rich understanding of the cytokines, receptors, signal transduction pathways, and transcription factors involved in Th1 differentiation. Although the picture is still incomplete, the basic pathways leading to Th1 differentiation can now be understood in in vitro and a number of infection and disease models.