Pathogenic Th2 (Tpath2) cells in airway inflammation

Immunological memory is a hallmark of adaptive immunity. Memory CD4 T cells function as a control tower of the adaptive immune system to direct immune responses, leading to the elimination of various invaded microorganisms. Important roles of functionally distinct CD4 helper T cell (Th) subsets, such as Th1, Th2 and Th17 cells, in the host-defense immune responses have been well recognized. In addition, however, these Th cell subsets are known to be involved in the pathogenesis of various chronic inflammatory diseases, including asthma. We recently identified an IL-5-producing highly pathogenic population in memory Th2 cells in allergic asthma [1, 2]. We named this population " memory-type pathogenic Th2 (Tpath2) cells " in airway inflammation. Other investigators also reported distinct Th2 cell populations, which produce a substantial amount of IL-5 or multiple cytokines in addition to IL-4 and IL-13 [3, 4]. These populations appear to be responsible for the pathology of various Th2-type chronic inflammatory diseases. Phenotypic and functional heterogeneity is recognized in memory CD4 T cells, while the roles for each population in the pathogenesis of inflammatory diseases have not yet been well analyzed. Recent studies on the functional clarification of memory Th2 cell subpopulations identified that distinct IL-5-producing memory-type Th2 cell subpopulations induced eosinophilic inflammation such as allergic airway inflammation and chronic skin inflammation [1, 3]. Chronic airway inflammation, in particular especially steroid-resistant airway inflammation, is induced experimentally not only by Th2 cells but also by Th17 cells. IL-17-producing Th2 cells increased in the inflammatory lung tissue and persisted during the chronic stage of asthma [4]. This subset appears to be another type of pathogenic Th2 cells. Thus, memory-type Th2 subpopulations appear to contribute to the pathogenesis and persistence of chronic airway inflammation such as chronic asthma and chronic skin inflammation. The understanding of the cellular and molecular mechanisms that control the development of these pathogenic subpopulations could be essential for the establishment of curative therapies of intractable allergic diseases. We have recently shown that IL-33 confers the pathogenicity of memory Th2 cells by inducing p38 mitogen-activated protein kinase (MAPK) activation [5]. The expression of ST2 (a component of IL-33 receptor) is predominantly detected on memory Th2 cells and dramatically elevated after the exposure to IL-33. IL-33 enhanced IL-5 production in memory Th2 cells. IL-33-induced IL-5 upregulation and increased expression of ST2 was not observed in either effector Th2 cells or effector and memory Th1 cells. IL-33-ST2 signaling upregulated …