B220+ Double-Negative T Cells Suppress Polyclonal T Cell Activation by a Fas-Independent Mechanism That Involves Inhibition of IL-2 Production

Abstract

Fas-mediated apoptosis is a key mechanism for elimination of autoreactive T cells, yet loss of function mutations in the Fas signaling pathway does not result in overt T cell-mediated autoimmunity. Furthermore, mice and humans with homozygous Faslpr or Fas ligandgld mutations develop significant numbers of B220+ CD4− CD8− double-negative (DN) αβ T cells (hereafter referred to as B220+ DN T cells) of poorly understood function. In this study, we show that B220+ DN T cells, whether generated in vitro or isolated from mutant mice, can suppress the ability of activated T cells to proliferate or produce IL-2, IL-10, and IFN-γ. B220+ DN T cells that were isolated from either lpr or gld mice were able to suppress proliferation of autologous and syngeneic CD4 T cells, showing that suppression is Fas independent. Furthermore, restoration of Fas/Fas ligand interaction did not enhance suppression. The mechanism of suppression involves inhibition of IL-2 production and its high affinity IL-2R α-chain (CD25). Suppression also requires cell/cell contact and TCR activation of B220+ DN T cells, but not soluble cytokines. These findings suggest that B220+ DN T cells may be involved in controlling autoreactive T cells in the absence of Fas-mediated peripheral tolerance.