A Lysosomal Protein Negatively Regulates Surface T Cell Antigen Receptor Expression by Promoting CD3ζ-Chain Degradation

Rika Ouchida, Sho Yamasaki, Masaki Hikida, Keiji Masuda, Kiyoko Kawamura, Akihiko Wada, Shigenobu Mochizuki, Masatoshi Tagawa, Akemi Sakamoto, Masahiko Hatano, Takeshi Tokuhisa, Haruhiko Koseki, Takashi Saito, Tomohiro Kurosaki, Ji Yang Wang

    Research output: Contribution to journalArticlepeer-review

    45 Citations (Scopus)

    Abstract

    Modulation of surface T cell antigen receptor (TCR) expression is an important mechanism for the regulation of immune responses and the prevention of T cell hyperactivation and autoimmunity. The TCR is rapidly internalized after antigen stimulation and then degraded in lysosomes. However, few of the molecules involved in this process have been identified. We demonstrate that the lysosomal protein LAPTM5 negatively regulated surface TCR expression by specifically interacting with the invariant signal-transducing CD3ζ chain and promoting its degradation without affecting other CD3 proteins, CD3ε, CD3δ, or CD3γ. TCR downmodulation required the polyproline-tyrosine motifs and the ubiquitin-interacting motif of LAPTM5. LAPTM5 deficiency resulted in elevated TCR expression on both CD4+CD8+ thymocytes and spleen T cells after CD3 stimulation, as well as enhanced T cell responses in vitro and in vivo. These results identify a lysosomal protein important for CD3ζ degradation and illustrate a unique mechanism for the control of surface TCR expression and T cell activation.

    Original languageEnglish
    Pages (from-to)33-43
    Number of pages11
    JournalImmunity
    Volume29
    Issue number1
    DOIs
    Publication statusPublished - Jul 18 2008

    All Science Journal Classification (ASJC) codes

    • Immunology and Allergy
    • Immunology
    • Infectious Diseases

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