Hyporesponsiveness of CD4 T cells induced in oral tolerance is maintained by selective impairment in the TCR-induced calcium/NFAT signaling pathway resulting from caspase activation.
We examined intracellular signaling of hyporesponsive CD4 T cells induced by continuous feeding with high-dose antigen in a TCR transgenic mouse system. The results demonstrated a selective impairment in their TCR-induced calcium/NFAT-signaling pathway. Proteomic analysis revealed caspase activation in these cells, which resulted in cleavage of GADS. Further analysis of the TCR-signaling complex showed that GADS-LAT-SLP-76-associated PLC-gamma1 was decreased in both phosphorylation and association. Thus, as a consequence of caspase activation, orally tolerant CD4 T cells could not form normal TCR signaling complexes associated with GADS and showed downregulated PLC-gamma1 activation, which resulted in impairment of TCR-induced calcium signaling.
Hachimura
Satoshi
S
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. ahachi@mail.ecc.u-tokyo.ac.jp
Kaji
Tomohiro
T
Asai
Kazumi
K
Ise
Wataru
W
Nakayama
Toshinori
T
Kaminogawa
Shuichi
S
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002118:Calcium / Q000502:physiology*; D020169:Caspases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000502:physiology*; D004789:Enzyme Activation; D007108:Immune Tolerance; D018928:Immunity, Mucosal; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C498726:Mona protein, mouse; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D020169:Caspases; D002118:Calcium