A subclass of dendritic cells kills CD4 T cells via Fas/Fas-ligand-induced apoptosis.

Abstract

SummaryDendritic cells (DC), the most efficient antigen-presenting cells, are well equipped for activation of naive CD4 + T cells by their expression of high levels of major histocompatibility complex and costimulator molecules. We now demonstrate that some DC are equally well equipped for killing these same T cells. Murine splenic DC consist of both conventional CDSot-DC and a major population of CD8cx + DC. Whereas CDS-DC induce a vigorous proliferative response in CD4 T cells, CD8 + DC induce a lesser response that is associated with marked T cell apoptosis. By using various mixtures of T cells and DC from Fas-mutant Ipr/Ipr mice and Fas-ligand (FasL) mutant gld/gld mice, we show this death is due to interaction of Fas on activated T cells with FasL on CD8 + DC. Furthermore, we show by direct surface staining that CD8 + DC, but not CD8-DC, express FasL at high levels. These findings indicate that FasL + CD8 + DC are a specialized subgroup of DC with a role in the regulation of the response of primary peripheral T cells.

Switching from a restricted to an effective CD4 T cell response by activating CD8+ murine dendritic cells with a Toll-like receptor 9 ligand

“…Earlier studies from this laboratory documented several ways in which CD8 + DC, freshly isolated from non-infected steady state mice, limited the proliferative response of interacting T cells, compared to CD8 -DC [28,29]. We now confirm that freshly isolated CD8 + DC induce poor CD4 T cell proliferation compared to CD8 -DC in a variety of antigen presentation assays, across a broad range of antigen concentrations and DC doses.…”

“…We compared normal DC with DC from FasL-mutant C3H/HeJ.gld mice [35]. A selective staining of CD8 + DC was obtained as in the previous study [28], but the same strong staining was obtained with CD8 + DC from the FasL-mutant C3H/ HeJ.gld mice, suggesting an unspecific staining (data not shown). It was concluded that freshly isolated splenic CD8 + DC did not express conventional FasL, despite their selective binding of a Fas-Fc construct.…”

“…In earlier studies from this laboratory [28] the reduced CD4 T cell proliferative response when stimulated by CD8 + DC rather than CD8 -DC appeared to be due to an increased rate of death in the activated T cells. This in turn was attributed to a Fas-FasL interaction because of the following observations: (i) The difference in CD4 T cell response to CD8 + versus CD8 -DC disappeared when Fas-deficient C3H/HeJ.lpr CD4 T cells were used; (ii) CD8 + DC showed a markedly increased binding of a Fas-Fc construct, which was used since no anti-FasL mAb was then available.…”

“…To verify and to extend earlier observations based on alloresponses, where only CD8 + and double-negative (DN) DC were compared [28], the capacity of the three splenic DC subsets from C57BL/6 mice to induce T cell proliferation was analysed using three different sources of Figure 1. CD8 + DC induce a lower CD4 T cell proliferation and IFN-c production than the other DC subsets.…”

“…Furthermore, not only did CD4 T cells proliferate poorly in response to CD8 + DC, they produced only very low levels of IFN-c, indicating a weak effector function. In our earlier study [28], the poor CD4 T cell proliferation induced by CD8 + DC was attributed to the death of Fasbearing activated CD4 T cells induced by CD8 + DC expressing Fas ligand (FasL). We now show that this conclusion was incorrect and document the absence of conventional FasL on CD8 + DC.…”