Antigen-induced unresponsiveness results in altered T cell signaling

Pretransplant exposure to allogeneic lymphocytes can result in donor-specif ic unresponsiveness and prolonged allograft survival. Intracellular signali ng events have been described in anergic T cell clones, but the biochemical events underlying in vivo induced unresponsiveness have not been studied i n detail. We employed a TCR transgenic mouse, bearing the ZC TCR, providing adequate numbers of homogenous peripheral T cells to study biochemical asp ects of T cell unresponsiveness in vivo. 2C mice exposed to semiallogeneic lymphocytes (H-2(b) x H-2(d)) experienced prolonged H-2d cardiac allograft survival, and cells from these mice did not proliferate or make IL-2 in res ponse to alloantigen (H-2d). Importantly, there were marked differences in TCR-associated tyrosine phosphorylation activation patterns, The targets fo r the unresponsive state appear to be diminished Lck activation and absent ZAP-70 and LAT (linker for activation of T cells) phosphorylation, Our stud y demonstrates that Ag-induced tolerance in vivo is accompanied by altered early TCR-mediated signaling events.