Males with X-linked severe combined immunodeficiency (XSCID) have defects in the common cytokine receptor gamma chain (gamma c) gene that encodes a shared, essential component of the receptors of interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15. The Janus family tyrosine kinase Jak3 is the only signaling molecule known to be associated with gamma c, so it was hypothesized that defects in Jak3 might cause an XSCID-like phenotype. A girl with immunological features indistinguishable from those of XSCID was therefore selected for analysis. An Epstein-Barr virus (EBV)-transformed cell line derived from her lymphocytes had normal gamma c expression but lacked Jak3 protein and had greatly diminished Jak3 messenger RNA. Sequencing revealed a different mutation on each allele: a single nucleotide insertion resulting in a frame shift and premature termination in the Jak3 JH4 domain and a nonsense mutation in the Jak3 JH2 domain. The lack of Jak3 expression correlated with impaired B cell signaling, as demonstrated by the inability of IL-4 to activate Stat6 in the EBV-transformed cell line from the patient. These observations indicate that the functions of gamma c are dependent on Jak3 and that Jak3 is essential for lymphoid development and signaling.

IL-23 and Th17 cells not only induce Th17-cell-mediated neutrophilic airway inflammation but also up-regulate Th2-cell-mediated eosinophilic airway inflammation.

In order to determine the role of CD4+ and CD8+ T-cells and of interleukin-5 (IL-5) in causing antigen-induced eosinophil infiltration into the site of airway late-phase reaction, we examined the effect of the in vivo depletion of CD4+ and CD8+ T-cells on the eosinophil infiltration of the trachea induced by antigen inhalation in mice. We also studied the effect of anti-murine IL-5 monoclonal antibody (mAb) on the antigen-induced eosinophil infiltration in the trachea. The eosinophil infiltration into the trachea of ovalbumin (OVA)-sensitized BALB/c mice began to increase 9 h after OVA inhalation and persisted for more than 48 h. The in vivo depletion of CD4+ T-cells by pretreatment with anti-L3T4 mAb significantly decreased the eosinophil infiltration induced by OVA inhalation in the trachea of sensitized mice. However, the in vivo depletion of CD8+ T-cells by pretreatment with anti-Lyt-2 mAb had no significant effect on OVA-induced eosinophil infiltration in the trachea. Pretreatment with anti-murine IL-5 mAb also decreased OVA-induced eosinophil infiltration in the trachea. In contrast, neither disodium cromoglycate nor a selective antagonist for platelet-activating factor CV-6209 decreased OVA-induced airway eosinophilia in the mouse. Our results provide direct evidence that CD4+ but not CD8+ T-cells mediate antigen-induced eosinophil recruitment in the airways and that IL-5 mediates this eosinophil recruitment.

It has recently been shown that interleukin (IL)-21 is produced by Th17 cells, functions as an autocrine growth factor for Th17 cells, and plays critical roles in autoimmune diseases. In this study, we investigated the differentiation and characteristics of IL-21–producing CD4+ T cells by intracellular staining. Unexpectedly, we found that under Th17-polarizing conditions, the majority of IL-21–producing CD4+ T cells did not produce IL-17A and -17F. We also found that IL-6 and -21 potently induced the development of IL-21–producing CD4+ T cells without the induction of IL-4, IFN-γ, IL-17A, or IL-17F production. On the other hand, TGF-β inhibited IL-6– and IL-21–induced development of IL-21–producing CD4+ T cells. IL-2 enhanced the development of IL-21–producing CD4+ T cells under Th17-polarizing conditions. Finally, IL-21–producing CD4+ T cells exhibited a stable phenotype of IL-21 production in the presence of IL-6, but retained the potential to produce IL-4 under Th2-polarizing conditions and IL-17A under Th17-polarizing conditions. These results suggest that IL-21–producing CD4+ T cells exhibit distinct characteristics from Th17 cells and develop preferentially in an IL-6–rich environment devoid of TGF-β, and that IL-21 functions as an autocrine growth factor for IL-21–producing CD4+ T cells.

We have analyzed the immune system in Stat5-deficient mice. Although Stat5a−/− splenocytes have a partial defect in anti-CD3-induced proliferation that can be overcome by high dose interleukin (IL)-2, we now demonstrate that defective proliferation in Stat5b−/− splenocytes cannot be corrected by this treatment. Interestingly, this finding may be at least partially explained by diminished expression of the IL-2 receptor β chain (IL-2Rβ), which is a component of the receptors for both IL-2 and IL-15, although other defects may also exist. Similar to the defect in proliferation in activated splenocytes, freshly isolated splenocytes from Stat5b−/− mice exhibited greatly diminished proliferation in response to IL-2 and IL-15. This results from both a decrease in the number and responsiveness of natural killer (NK) cells. Corresponding to the diminished proliferation, basal as well as IL-2– and IL-15–mediated boosting of NK cytolytic activity was also greatly diminished. These data indicate an essential nonredundant role for Stat5b for potent NK cell–mediated proliferation and cytolytic activity.

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SummaryWe have previously shown that antigen-induced eosinophil recruitment into the tissue of sensitized mice is mediated by CD4 + T cells and interleukin 5. To determine whether interferon 3' ) regulates antigen-induced eosinophll recruitment into the tissue, we studied the effect of recombinant (r) murine IFN-3, and of anti-IFN-3, monoclonal antibody (mAb) on the eosinophil infiltration of the trachea induced by antigen inhalation in mice. The intraperitoneal administration of rlFN-3, prevented antigen-induced eosinophil infiltration in the trachea of sensitized mice. The administration of rIFN-3, also decreased antigen-induced CD4 + T cell but not CD8 + T cell infiltration in the trachea. On the other hand, pretreatment with anti-IFN-'y mAb enhanced antigen-induced eosinophil and CD4 + T cell infiltration in the trachea. These results indicate that IFN-3, regulates antigen-induced eosinophil recruitment into the tissue by inhibiting CD4 + T cell infiltration. Eosinophil infiltrate is a characteristic feature of allergic inflammation such as asthma. In a murine model of airway late-phase reaction, we have previously shown that antigeninduced eosinophil recruitment into the tissue of sensitized mice is mediated by CD4 + T cells and IL-5 (1). However, the mechanism that regulates antigen-induced eosinophil recruitment into the tissue is unknown. It has been suggested that CD4 + Th cells can be divided into two subsets (Thl and Th2 cells) on the basis of their different patterns of cytokine secretion (2); Thl cells produce Ib2, IFN-3,, and lymphotoxin, and Th2 cells produce Ib4, IL-5, and Ib6. Furthermore, IFN-3, has been shown to be a major regulatory cytokine that inhibits the proliferation of Th2 cells in vitro (3, 4) and antagonizes the in vivo Th2-type responses such as IL-4-dependent IgE antibody production (5). Therefore, to determine whether IFN-3, regulates antigen-induced eosinophil recruitment into the tissue, we studied the effect of recombinant murine IFN-3' and of anti-IFN-3, mAb on the eosinophil infiltration of the trachea induced by antigen inhalation in mice. Our results indicate that IFN-3, regulates antigen-induced eosinophil recruitment into the tissue by inhibiting CD4 § T cell infiltration. Materials and Methods Mice and Immunization. 8-wk-old BALB/c mice (Charles RiverLaboratories, Shizuoka, Japan) were immunized intraperitoneally twice with 1 #g of OVA (Sigma Chemical Co., St. Louis, MO) in 4 mg of aluminum hydroxide at a 2-wk interval. 10-14 d after the second immunization, the sensitized mice were challenged with aerosolized OVA as described below. Antigen-induced Eosinophil lnfihration in Mouse Trachea.The eosinophil infiltration into the trachea was induced by the inhalation of antigen in sensitized mice, and the number of eosinophils infiltrating into the submucosal tissue of trachea was evaluated as described previously (1). Briefly, the sensitized mice inhaled aerosolized OVA (50 mg/ml) dissolved in 0.9% saline by a nebulizer (646; DeVilbiss Corp., Somerset, PA) for 20 min. As a...

Airway hypersensitive reaction (AHR) is an animal model for asthma, which is caused or