Transitional dendritic cells (tDCs) are an evolutionarily conserved dendritic cell subset that shares phenotypic and transcriptional features with plasmacytoid DCs (pDCs) and type 2 DCs (DC2s), yet their functions in vivo remain poorly understood. Although tDCs arise within a pDC-related developmental lineage, they exhibit functions distinct from those of pDCs. Following viral sensing, tDCs produce IL-1β rather than the high levels of type I interferon characteristic of pDCs. During murine coronavirus infection, depletion of pDCs results in severe disease associated with elevated systemic IL-1β, whereas combined depletion of pDCs and tDCs ameliorates pathology. Furthermore, IL-1β blockade reduces disease severity in pDC-depleted mice, supporting a pathogenic role for tDC-derived IL-1β in the absence of pDCs.
Beyond their role in innate immunity, tDCs can acquire the antigen-presenting features of DC2s, raising the possibility that they also regulate adaptive immune responses. Using mouse models of combined pDC/tDC depletion, we observed a significant reduction in antigen-specific T follicular helper cells (Tfh), germinal center B cells, and antibody responses following immunization with ovalbumin-coupled sheep red blood cells (SRBC-OVA), despite preservation of Notch2-dependent ESAM+ DC2s. Because these models deplete both pDCs and tDCs, we used mice with selective depletion of tDCs to determine whether tDC loss was responsible for these defects. Selective tDC depletion phenocopied the defects observed following combined pDC/tDC depletion. Together, these findings establish tDCs as functionally specialized members of the pDC-related lineage that shape innate responses to viral infection and promote Tfh differentiation, germinal center formation, and antibody production following immunization.