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

Abstract

RelB is an NF-κB family transcription factor activated in the noncanonical pathway downstream of NF-κB-inducing kinase (NIK) and TNF receptor family members including lymphotoxin-β receptor (LTβR) and CD40. Early analysis suggested that RelB is required for classical dendritic cell (cDC) development based on a severe reduction of cDCs in <i>Relb</i>^-/- mice associated with profound myeloid expansion and perturbations in B and T cells. Subsequent analysis of radiation chimeras generated from wild-type and <i>Relb</i>^-/- 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 LTβR-dependent subset of splenic CD4⁺ cDC2s. These results identify a relatively restricted role of RelB in DC development. Moreover, the myeloid expansion in <i>Relb</i>^-/- 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.