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-γ1 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-γ1 activation, which resulted in impairment of TCR-induced calcium signaling.