Fantastic new insight into mechanisms of lung T H2 responses

Abstract

The understanding of the complex steps that occur during the development of TH2 responses remains incomplete, largely because of the apparent overlapping function of rare cells. For example, while it is appreciated that CD4 T cells are a major source of IL-4, the contribution of NKT cells, eosinophils, basophils, and mast cells is unclear. To examine the orchestration of TH2 immunity in the lung, the investigators used experimental infection of mice with the nematode Nippostrongylus brasiliensis (Np). The investigators took advantage of mice containing a bicistronic knock-in IL-4 gene linked via an internal ribosomal entry site (IRES) with enhanced green fluorescent protein; these mice, designated 4get, allow easy identification of IL-4–producing cells. Using these animals, the investigators demonstrate that eosinophils are the predominant source of IL-4, followed by TH2 cells and basophils (mast cells and NKT cells failed to make substantial levels of IL-4 in their system). To further characterize eosinophils and basophils—cell types that have not been understudied at a molecular level—the investigators purified both populations of cells from the Np-challenged lungs. Microarray analysis of RNA transcripts expressed in both cell types revealed more than 1000 genes that were differentially expressed between the 2 cell types. Indeed, some very interesting genes were identified, including (a) CCR3, CD11c, CD24, GATA1, and IL27 (all expressed only by eosinophils) and (b) GATA2, 2B4, H4 receptor, IL-18 receptor, and a variety of cytokines (all expressed only by basophils). The investigators subsequently examined the signals required for recruitment of both cell types into the Np-infected lung. Eosinophil and basophil expansion in the blood and their capacity to express IL-4 were independent of Stat6 and T cells. In contrast, eosinophil (and TH2 cell) recruitment to the lung was dependent on Stat6 expression by a bone marrow–derived tissue-resident cell. However, basophil recruitment was Stat6-independent (and IL-4/IL-13–independent) but T cell–dependent. Taken together, these results show that innate production of IL-4 by basophils and eosinophils makes a substantial contribution to TH2 lung responses and that diverse mechanisms orchestrate recruitment of these cells to the lung. The understanding of the complex steps that occur during the development of TH2 responses remains incomplete, largely because of the apparent overlapping function of rare cells. For example, while it is appreciated that CD4 T cells are a major source of IL-4, the contribution of NKT cells, eosinophils, basophils, and mast cells is unclear. To examine the orchestration of TH2 immunity in the lung, the investigators used experimental infection of mice with the nematode Nippostrongylus brasiliensis (Np). The investigators took advantage of mice containing a bicistronic knock-in IL-4 gene linked via an internal ribosomal entry site (IRES) with enhanced green fluorescent protein; these mice, designated 4get, allow easy identification of IL-4–producing cells. Using these animals, the investigators demonstrate that eosinophils are the predominant source of IL-4, followed by TH2 cells and basophils (mast cells and NKT cells failed to make substantial levels of IL-4 in their system). To further characterize eosinophils and basophils—cell types that have not been understudied at a molecular level—the investigators purified both populations of cells from the Np-challenged lungs. Microarray analysis of RNA transcripts expressed in both cell types revealed more than 1000 genes that were differentially expressed between the 2 cell types. Indeed, some very interesting genes were identified, including (a) CCR3, CD11c, CD24, GATA1, and IL27 (all expressed only by eosinophils) and (b) GATA2, 2B4, H4 receptor, IL-18 receptor, and a variety of cytokines (all expressed only by basophils). The investigators subsequently examined the signals required for recruitment of both cell types into the Np-infected lung. Eosinophil and basophil expansion in the blood and their capacity to express IL-4 were independent of Stat6 and T cells. In contrast, eosinophil (and TH2 cell) recruitment to the lung was dependent on Stat6 expression by a bone marrow–derived tissue-resident cell. However, basophil recruitment was Stat6-independent (and IL-4/IL-13–independent) but T cell–dependent. Taken together, these results show that innate production of IL-4 by basophils and eosinophils makes a substantial contribution to TH2 lung responses and that diverse mechanisms orchestrate recruitment of these cells to the lung.