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

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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.
Funding Information
  • National Institute of General Medical Sciences (R35GM145290)
  • National Institute of Allergy and Infectious Diseases (R21AI168668)

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