Deficiency of transcription factor RelB perturbs myeloid and DC development by hematopoietic-extrinsic mechanisms

RelB is an NF-kappa B family transcription factor activated in the noncanonical pathway downstream of NF-kappa B-inducing kinase (NIK) and TNF receptor family members including lymphotoxin-beta receptor (LT beta R) and CD40. Early analysis suggested that RelB is required for classical dendritic cell (cDC) development based on a severe reduction of cDCs in Relb(-/-) mice associated with profound myeloid expansion and perturbations in B and T cells. Subsequent analysis of radiation chimeras generated from wild-type and Relb(-/-) bone marrow showed that RelB exerts cell-extrinsic actions on some lineages, but it has remained unclear whether the impact of RelB on cDC development is cell-intrinsic or -extrinsic. Here, we reevaluated the role of RelB in cDC and myeloid development using a series of radiation chimeras. We found that there was no cell-intrinsic requirement for RelB for development of most cDC subsets, except for the Notch2- and LT beta R-dependent subset of splenic CD4(+) cDC2s. These results identify a relatively restricted role of RelB in DC development. Moreover, the myeloid expansion in Relb(-/-) mice resulted from hematopoietic-extrinsic actions of RelB. This result suggests that there is an unrecognized but critical role for RelB within the nonhematopoietic niche that controls normal myelopoiesis.