In a report that challenges existing ideas, Ohnmacht et al. find that depleting mice of their dendritic cells (DCs) leads to severe autoimmunity (page 549).
Earlier studies concluded that DCs weren't essential defenders against autoimmunity because mice were hardly affected by DC deletions. Although these cells help eliminate autoreactive lymphocytes in the thymus, B cells and other antigen-presenting cells (APCs) can do this too, suggesting that other APCs can compensate for the absence of DCs.
Here, Ohnmacht et al. find just the opposite. In mice born missing more than 90% of their DCs, over half died within the first few months of life from sudden and severe autoimmunity. Without DCs in the thymus, autoreactive T cells escaped into the periphery where they went unregulated. The authors also noted elevated levels of autoreactive CD4 T cells and autoantibodies within various inflamed tissues, which were presumably primed by the few remaining DCs and other types of APCs in the tissues. Th1 and Th17 cells, both known to contribute to autoimmune inflammation, were also elevated compared with controls.
Why previous studies reached different conclusions may be a matter of timing and technical detail. In some earlier experiments, DCs had been eliminated transiently during adult life, at which point most autoreactive T cells may already have been deleted in the thymus. And although the authors of the most recent study used a similar technique to eliminate DCs, they failed to get rid of all types of DCs, notably leaving Langerhans cells and plasmacytoid DCs behind.
How DCs enforce self-tolerance in the periphery remains elusive. The quantity of regulatory T cells did not appear to change in the DC-deficient mice, indicating that changes in these inflammation suppressors were not behind the autoimmunity. However, peripheral DCs may be a source of IL-10 or TGF-β, proteins required to maintain self-tolerance.
