Changes in sensitivity of peripheral lymphocytes of autoimmune gld mice to FasL-mediated apoptosis reveal a mechanism for the preferential deletion of CD4-CD8-B220+ T cells

S. Xiao
2004 International Immunology  
During thymic selection'mis-selected' CD8 + T cells exit to the periphery where they are deleted by a Fas/FasL-mediated mechanism, presumably as a result of activation by self-antigens. In the absence of functional FasL, as is the case in autoimmune gld mice, these'mis-selected' T cells develop into unique Thy1 + CD4 ± CD8 ± TCRab + B220 + lymphocytes [abnormal double negative T (DN T) cells]. Using bioactive FasL-bearing vesicles [FasL vesicle preparation (FasL VP)], we were able to induce
more » ... able to induce acute apoptosis in freshly isolated lymphocytes and to demonstrate that peripheral lymphocytes of gld mice become more sensitive to the FasL-mediated apoptosis as they age. Furthermore,¯ow cytometric analyses indicated that within this peripheral lymphocyte population, the abnormal DN T cells were preferentially eliminated. The exquisite sensitivity of these abnormal DN T cells is attributed to their increased membrane Fas expression with a concomitant reduction of cytosolic FLIP L . Our data support the hypothesis that speci®c components of the Fas-mediated apoptotic pathway are modulated in favor of the elimination of auto-reactive T cells as well as those CD8 + T cells that are'mis-selected' in the thymus and escape to the periphery. as the death-inducing signaling complex (DISC) (8±10). Concentrated procaspase-8 in DISC initiates an autoactivation process that generates active caspase-8. Depending on the activation of caspase 8 or the participation of mitochondria, an acute (type I) or a slow (type II) apoptosis pathway can be activated (11, 12) . Both apoptosis processes, however, can be inhibited by FLICE/caspase-8 inhibitory protein (FLIP), which competitively inhibits the binding of procaspase-8 to FADD before the bifurcation of the type I and Correspondence
doi:10.1093/intimm/dxh078 pmid:15096479 fatcat:dhgybbzyajfv5dfntwshs4fipq