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Negative feedback of T cell activation through inhibitory adapters and costimulatory receptors
Author(s) -
Saito Takashi,
Yamasaki Sho
Publication year - 2003
Publication title -
immunological reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.839
H-Index - 223
eISSN - 1600-065X
pISSN - 0105-2896
DOI - 10.1034/j.1600-065x.2003.00022.x
Subject(s) - t cell receptor , biology , microbiology and biotechnology , cd28 , t cell , receptor , cytotoxic t cell , btla , immunological synapse , signal transduction , jurkat cells , immune receptor , immune system , immunology , biochemistry , in vitro
Summary: 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 76 kDa (SLP‐76) or Gab2 by zeta‐associated protein of 70 kDa (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 induces 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.