Involvement of CD4 D3-D4 membrane proximal extracellular domain for the inhibitory effect of oxidative stress on activation-induced CD4 down-regulation and its possible role for T cell activation

During antigen presentation, CD4 functions to stabilize T cell receptor (TCR)-class II MHC interactions and coordinate Ag-induced T cell activation signals. These activation signals cause CD4 down-regulation, presumably acting to optimize T cell activation. We previously reported that oxidative stress interferes with activation-induced CD4 down-regulation in T cells. In this study, we have further investigated inhibition of CD4 down-regulation by oxidative stress and its role for T cell activation. A construct comprised of the mouse FcgammaRIIB extracellular domain and the transmembrane/cytoplasmic domains of human CD4 (FcgammaR/CD4) was expressed in a human T cell line. Oxidant actually potentiated down-regulation of the FcgammaR/CD4 chimera and induced Lck dissociation from both CD4 and FcgammaR/CD4, which is a crucial intracellular process for activation-induced CD4 down-regulation, suggesting a critical role of CD4 ectodomain in the inhibition of CD4 down-regulation by oxidative stress. Furthermore, insertion of CD4 D3-D4 membrane proximal extracellular region between FcgammaR extracellular domain and CD4 transmembrane/cytoplasmic domains in FcgammaR/CD4 chimera made this molecule behave like native CD4 molecule under oxidative stress condition. These data imply that the inhibitory effect of oxidative stress on CD4 down-regulation is executed via D3-D4 domain of CD4 ectodomain. As to its role for T cell activation, CD4 coaggregation with CD3 under the oxidative conditions enhanced activation signal induced by CD3 aggregation. Our results demonstrate that Ag-induced T cell activation which is normally concomitant with CD4 down-regulation may be disturbed through the aberrant regulation of CD4 expression by oxidative stress. (C) 2003 Elsevier Science Ltd. All rights reserved.