Memory-type ST2+CD4+ T cells participate in the steroid-resistant pathology of eosinophilic pneumonia

Abstract

The lung develops an unique epithelial barrier system to protect host from continuous invasion of various harmful particles. Interleukin (IL-)33 released from epithelial cells in the lung drives the type 2 immune response by activating ST2− expressed immune cells in various allergic diseases. However, the involvement of memory-type ST2+CD4+ T cells in such lung inflammation remains unclear. Here we demonstrated that intratracheal administration of IL-33 resulted in the substantial increase of numbers of tissue-resident memory-type ST2+CD4+ T cells in the lung. Following enhanced production of IL-5 and IL-13, eosinophilic lung inflammation sequentially developed. IL-33-mediated eosinophilic lung inflammation was not fully developed in T cell-deficient Foxn1 nu mice and NSG mice. Dexamethasone treatment showed limited effects on both the cell number and function of memory-type ST2+CD4+ T cells. Thus our study provides novel insight into the pathogenesis of eosinophilic lung disease, showing that memory-type ST2+CD4+ T cells are involved in IL-33-induced eosinophilic inflammation and elicited steroid-resistance.

PPAR-γ in innate and adaptive lung immunity

“…These results were corroborated by recent evidence that identified PPAR‐γ as well as CRTh2, IL‐5, and IL‐9 to be highly expressed in a subset of memory Th2 cells are only present in allergic individuals . The importance of this discovery was further highlighted by evidence that this highly pathogenic Th2 subset is potentially one of the main factors driving steroid‐resistant asthma, a key health problem associated with the treatment of this disease . Interestingly, there is evidence that PPAR‐γ might mediate control of Th2 pathogenicity also via regulation of CD4 + T cell intrinsic metabolism because it has been shown to influence proliferation of memory Th2 cells in some settings .…”

“…40 The importance of this discovery was further highlighted by evidence that this highly pathogenic Th2 subset is potentially one of the main factors driving steroid-resistant asthma, a key health problem associated with the treatment of this disease. 41 Interestingly, there is evidence that PPAR-might mediate control of Th2 pathogenicity also via regulation of CD4 + T cell intrinsic metabolism because it has been shown to influence proliferation of memory Th2 cells in some settings. 42 Furthermore, induction of PPAR-expression after T cell activation was shown to be mediated by mTOR signaling 42 providing further evidence that the interaction between these 2 factors is of great importance in multiple cell types.…”

The pathogenicity of IL-33 on steroid-resistant eosinophilic inflammation via the activation of memory-type ST2+CD4+ T cells

“…Those CD44 + ST2 + CD4 + T cells showed an increased ability to produce Th2 cytokines, such as IL‐5 and IL‐13, upon anti‐TCR stimulation (Fig. ) . Both ILC2s and ST2 + CD4 + T cells responded to IL‐33 in the lung tissue; however, a distinct pattern in the time course of activation of each cell population was observed.…”

“…ILC2s preferentially reside in the lung and produce large amounts of Th2 cytokines, such as IL‐5 and IL‐13, in response to IL‐33, IL‐25, and thymic stromal lymphopoietin (TSLP) in a synergistic manner . ST2 + CD4 + T cells also reside in the lung with the high expression of CD44 and low expression of CD62L . Intratracheal administration of IL‐33 resulted in increased CD44 + ST2 + CD4 + T cells accompanied by the formation of lymphoid clusters.…”

“…TSLP stimulation induces steroid resistance in ILC2s, and the inhibition of the phosphorylation of STAT5 ameliorates steroid‐resistant inflammation . In the mouse model of eosinophilic lung inflammation induced by IL‐33, steroid treatment showed no influence on the infiltration of memory‐type ST2+CD4+ T cells that produced substantial amounts of IL‐5 and IL‐13 . Because IL‐33 activates p38‐MAPK in CD4+ T cells, IL‐33 would modulate GR‐signal transduction and prevent nuclear translocation via the phosphorylation of GR.…”