Males with X-linked severe combined immunodeficiency (XSCID) have defects in the common cytokine receptor γ chain (γ _c ) gene that encodes a shared, essential component of the receptors for 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 γ _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 γ _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 signacrcling, 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 γ _c are dependent on Jak3 and that Jak3 is essential for lymphoid development and signaling.

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 eosinophilla 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.

We 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 gamma (IFN-gamma) regulates antigen-induced eosinophil recruitment into the tissue, we studied the effect of recombinant (r) murine IFN-gamma and of anti-IFN-gamma monoclonal antibody (mAb) on the eosinophil infiltration of the trachea induced by antigen inhalation in mice. The intraperitoneal administration of rIFN-gamma prevented antigen-induced eosinophil infiltration in the trachea of sensitized mice. The administration of rIFN-gamma also decreased antigen-induced CD4+ T cell but not CD8+ T cell infiltration in the trachea. On the other hand, pretreatment with anti-IFN-gamma mAb enhanced antigen-induced eosinophil and CD4+ T cell infiltration in the trachea. These results indicate that IFN-gamma regulates antigen-induced eosinophil recruitment into the tissue by inhibiting CD4+ T cell infiltration.

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.