Tolerance or immunity — DCs decide

Researchers at the University of Queensland have shown that dendritic cells (DCs) that lack the NF-κB-family protein RELB (v-rel reticuloendotheliosis viral oncogene homologue B) and CD40 (tumour-necrosis factor receptor superfamily member 5, TNFRSF5) can suppress previously primed immune responses in vivo. According to their report, now published in Immunity, the DCs achieve this by inducing a population of CD4⁺ regulatory T (T_Reg) cells.

The molecular mechanisms that control the functions of DCs in tolerance and immunity are not well understood, and advances in this field are of particular interest owing to the possible therapeutic applications of such findings for the immunotherapy of autoimmune diseases. Previous work has indicated that the ability of DCs to induce tolerance or immunity in response to an antigen is linked to the maturation state of the cell, with immature DCs being able to induce T-cell anergy in vitro. RELB activity is known to be required for DC maturation. So here, Martin et al. investigated whether abrogating the function of RELB in DCs would be sufficient to enable these cells to suppress immune responses in vivo.

RelB ^−/− bone-marrow-derived DCs, which lack cell-surface expression of CD40, were pulsed with antigen and transferred into naive wild-type mice. The RelB^−/− DCs failed to prime an antigen-specific T-cell proliferative response in recipient mice, and they also suppressed a previously primed immune response when administered seven days after immunization. Similar results were obtained using DCs generated in the presence of BAY (a compound that blocks the nuclear translocation and activity of NF-κB-family proteins), which also lack CD40 expression, and with DCs from Cd40^−/− mice.

So, DCs in which RelB function is blocked lack expression of CD40 and can suppress primed immune responses in vivo — but, do they do this by deleting effector T cells or by inducing T_Reg cells in recipients? The authors investigated this by collecting CD4⁺ T cells from the spleens of mice that had been injected with antigen-pulsed BAY-treated DCs and transferring these T cells into primed recipient mice. Antigen-specific T-cell responses were suppressed in mice that received the CD4⁺ T cells. This shows that T_Reg cells were induced in the mice that received the treated DCs and that these T cells could transfer tolerance to recipient primed mice (a concept known as infectious tolerance). Further experiments showed that these T_Reg cells produced interleukin-10 (IL-10) in an antigen-specific manner, and that production of this cytokine was responsible for the observed suppression.

These results show that RELB, by controlling DC maturation and expression of CD40, could be important for determining the response of T cells to DCs in lymphoid organs, resulting in either tolerance or immunity.