Negative feedback of T cell activation through inhibitory adapters and costimulatory receptors.
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.
Saito
Takashi
T
Department of Molecular Genetics, Graduate School of Medicine, Chiba University, Chiba, Japan. saito@med.m.chiba-u.ac.jp
Yamasaki
Sho
S
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism; D060908:CTLA-4 Antigen; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D018448:Models, Immunological; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D002352:Carrier Proteins; C556707:Ctla4 protein, mouse; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; C498782:Sh3kbp1 protein, mouse