The E3 ligases Itch and WWP2 cooperate to limit T H 2 differentiation by enhancing signaling through the TCR

Daisuke Aki, Hui Li, Wen Zhang, Mingke Zheng, Chris Elly, Jee H. Lee, Weiguo Zou, Yun Cai Liu

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13 Citations (Scopus)


The mechanisms by which the sensitivity of naive CD4 + T cells to stimulation by the cognate antigen via the T cell antigen receptor (TCR) determines their differentiation into distinct helper T cell subsets remain elusive. Here we demonstrate functional collaboration of the ubiquitin E3 ligases Itch and WWP2 in regulating the strength of the TCR signal. Mice lacking both Itch and WWP2 in T cells showed spontaneous autoimmunity and lung inflammation. CD4 + T cells deficient in Itch and WWP2 exhibited hypo-responsiveness to TCR stimulation and a bias toward differentiation into the T H 2 subset of helper T cells. Itch and WWP2 formed a complex and cooperated to enhance TCR-proximal signaling by catalyzing the conjugation of atypical ubiquitin chains to the phosphatase SHP-1 and reducing the association of SHP-1 with the tyrosine kinase Lck. These findings indicate that targeted ubiquitination regulates the strength of the TCR signal and differentiation toward the T H 2 lineage.

Original languageEnglish
Pages (from-to)766-775
Number of pages10
JournalNature Immunology
Issue number7
Publication statusPublished - 2018 Jul 1
Externally publishedYes


ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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