Negative feedback of T cell activation through inhibitory adapters and costimulatory receptors

Takashi Saito, Sho Yamasaki

Research output: Contribution to journalReview articlepeer-review

63 Citations (Scopus)


Antigen recognition by the T cell receptor (TCR) complex induces the formation of a TCR signalosome by recruiting various signaling molecules, generating the recognition signals for T cell activation. The activation status and functional outcome are positively and negatively regulated by dynamic organization of the signalosome and by costimulation signals. We have studied the negative regulation of T cell activation, particularly through inhibitory adapters and costimulation receptors that are little expressed in resting cells but are induced upon T cell activation. We described Grb-associated binder 2 (Gab2) and cytotoxic T lymphocyte antigen-4 (CTLA-4) as a representative inhibitory adapter and a negative costimulation receptor, respectively, both of which exhibit negative feedback. Gab2 functions as a signal branch for activation vs. inhibition, as phosphorylation of either Src homology 2 (SH2) domain-containing leukocyte phosphoprotein of 76kDa (SLP-76) or Gab2 by zeta-associated protein of 70kDa (ZAP-70) determines the fate of the response. As a professional inhibitory receptor, CTLA-4 inhibits T cell response by competition of ligand binding with positive costimulator receptor CD28, and also reduces inhibitory signaling. The trafficking and the cell surface expression of CTLA-4 are dynamically regulated and induced. CTLA-4 is accumulated in lysosomes and secreted to the T cell-APC contact site upon TCR stimulation. As T cell activation proceeds, these inhibitory adapters and costimulation receptors are induced and suppress/regulate the responses as negative feedback.

Original languageEnglish
Pages (from-to)143-160
Number of pages18
JournalImmunological Reviews
Publication statusPublished - Apr 2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology


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