Pde1b controls cyclic nucleotide signaling in cDC1 and macrophages to regulate immune responses

Abstract Cyclic nucleotides cAMP and cGMP are potent suppressors of immune activation, yet how their intracellular levels are regulated within antigen-presenting myeloid cells remains undefined. Here we identify phosphodiesterase 1B (Pde1b) as a lineage-restricted regulator of cyclic nucleotide signaling in conventional type 1 dendritic cells (cDC1) and a subset of macrophages. Using genetic loss-of-function models and Listeria infection, we show that Pde1b is required for immune responses. Pde1b deficiency impairs bacterial clearance and reduces antigen-specific CD8+ and CD4 + T cell expansion, while myeloid transcriptional programs are skewed towards alternative and immunoregulatory states. These defects are largely attributable to DC dysfunction, as adoptive transfer of wild-type DC in Pde1b-deficient recipients partially rescues T cell priming. Macrophages exhibit parallel defects, including reduced frequency and impaired inflammatory and antimicrobial function. Mechanistically, Pde1b loss elevates cAMP and cGMP in cDC1 and macrophages, leading to increased PKA/PKG signaling and CREB-associated transcriptional reprogramming. Pharmacological inhibition of other phosphodiesterase families does not fully recapitulate Pde1b loss. Together, these findings identify Pde1b as a cell-type-specific regulator of cyclic nucleotide signaling essential for immune responses.