Natural helper cells and TH2-type innate immunity

Natural helper (NH) cells are a newly identified innate lymphocyte population, which respond to a combination of interleukin (IL)-2 and IL-25 or IL-33 to produce large amounts of TH2 cytokines, most notably, IL-5 and IL-13. We identified NH cells in lymphoid clusters in adipose tissues, which we termed fat-associated lymphoid clusters. IL-5 and IL-13 produced by activated NH cells induce eosinophilia and goblet cell hyperplasia, respectively, and play an important role in anti-helminth immunity and allergic diseases, such as asthma. In addition, NH cells produce TH2 cytokines constitutively in the absence of stimulation and support the self-renewal of B1 cells and IgA production by B cells. After our identification of NH cells, other groups have also reported novel TH2 cytokine-producing cells, such as nuocytes, and innate helper type 2 cells. There are similarities and differences between these newly identified cell populations and NH cells. Multipotent progenitor cell type 2 (MPP) cells can differentiate to other myeloid cells, making this a distinct cell type from the others. MPP cells, nuocytes, and innate helper type 2 cells respond to IL-25 alone in vivo, whereas NH cells do not respond to IL-25 without IL-2, although they respond strongly to IL-33. Localization of NH cells in fat-associated lymphoid clusters is an intriguing difference compared with the other cell types, which are found in the lymph node and/or spleen. This article summarizes current information regarding the emerging field of TH2-type innate lymphocytes.