Human Tyrosine Kinase 2 Deficiency Reveals Its Requisite Roles in Multiple Cytokine Signals Involved in Innate and Acquired Immunity

Yoshiyuki Minegishi, Masako Saito, Tomohiro Morio, Ken Watanabe, Kazunaga Agematsu, Shigeru Tsuchiya, Hidetoshi Takada, Toshiro Hara, Nobuaki Kawamura, Tadashi Ariga, Hideo Kaneko, Naomi Kondo, Ikuya Tsuge, Akihiro Yachie, Yukio Sakiyama, Tsutomu Iwata, Fumio Bessho, Tsutomu Ohishi, Kosuke Joh, Kohsuke ImaiKazuhiro Kogawa, Miwa Shinohara, Mikiya Fujieda, Hiroshi Wakiguchi, Srdjan Pasic, Mario Abinun, Hans D. Ochs, Eleonore D. Renner, Annette Jansson, Bernd H. Belohradsky, Ayse Metin, Norio Shimizu, Shuki Mizutani, Toshio Miyawaki, Shigeaki Nonoyama, Hajime Karasuyama

Research output: Contribution to journalArticlepeer-review

409 Citations (Scopus)

Abstract

Tyrosine kinase 2 (Tyk2) is a nonreceptor tyrosine kinase that belongs to the Janus kinase (Jak) family. Here we identified a homozygous Tyk2 mutation in a patient who had been clinically diagnosed with hyper-IgE syndrome. This patient showed unusual susceptibility to various microorganisms including virus, fungi, and mycobacteria and suffered from atopic dermatitis with elevated serum IgE. The patient's cells displayed defects in multiple cytokine signaling pathways including those for type I interferon (IFN), interleukin (IL)-6, IL-10, IL-12, and IL-23. The cytokine signals were successfully restored by transducing the intact Tyk2 gene. Thus, the Tyk2 deficiency is likely to account for the patient's complex clinical manifestations, including the phenotype of impaired T helper 1 (Th1) differentiation and accelerated Th2 differentiation. This study identifies human Tyk2 deficiency and demonstrates that Tyk2 plays obligatory roles in multiple cytokine signals involved in innate and acquired immunity of humans, which differs substantially from Tyk2 function in mice.

Original languageEnglish
Pages (from-to)745-755
Number of pages11
JournalImmunity
Volume25
Issue number5
DOIs
Publication statusPublished - Nov 2006

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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