IL‐12 receptor deficiency revisited: IL‐23‐mediated signaling is also impaired in human genetic IL‐12 receptor β1 deficiency

• Published in: European journal of immunology 2003-12, Vol.33 (12), p.3393-3397
• Main Authors: Hoeve, Marieke A., de Boer, Tjitske, Langenberg, Dennis M. L., Sanal, Ozden, Verreck, Frank A. W., Ottenhoff, Tom H. M.
• Format: Article
• Language: English
• Subjects: Cell‐mediated immunity; IFN‐γ induction; IL‐12Rβ1‐deficiency; Interleukin‐23; Mycobacterial infection
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200324343

IFN‐γ and IL‐12 are crucial cytokines for cell‐mediated immunity against intracellular pathogens. We have previously shown that human IL‐12Rβ1‐deficiency leads to impaired IL‐12 responsiveness and unusual susceptibility to infections due to mycobacteria and salmonellae. IL‐23 is a cytokine with functions that partially overlap with those of IL‐12. IL‐23 consists of IL‐12p40 and anovel p19 protein, and binds to a receptor complex comprising IL‐12Rβ1 and IL‐23R. Thus, IL‐12Rβ1‐deficiency may impair both IL‐12‐ and IL‐23 signaling, and both may contribute to the immunological phenotypes. To examine whether IL‐12Rβ1 is essential for IL‐23 signaling in human T cells, we have studied IL‐23 responsiveness of four IL‐12Rβ1‐deficient individuals. Whereas IL‐23promoted IFN‐γ production by CD4+ and CD8+ T cells in controls, IL‐12Rβ1‐deficient T cells lacked IL‐23‐induced IFN‐γ secretion, but responded normally to IL‐2, IL‐4, IL‐15 and IL‐18. We also show that induction of IFN‐γ production by IL‐23 depends upon TCR‐ligation and is enhanced by CD28‐costimulation. Furthermore, IL‐23 cooperates with IL‐12 and IL‐18 in promoting IFN‐γ production in controls, but not in patients. We conclude that IL‐12Rβ1‐deficiency impairs IL‐12‐ and IL‐23‐dependent signaling in human T cells. The syndrome caused by IL‐12Rβ1‐deficiency thus needs to be reinterpreted as resulting from defective IL‐12‐as well as IL‐23‐mediated immunity.