The adenylate cyclase toxin-hemolysin (CyaA, ACT, or AC-Hly) of targets phagocytic cells expressing the complement receptor 3 (CR3, Mac-1, αβ integrin, or CD11b/CD18). CyaA delivers into cells an N-terminal adenylyl cyclase (AC) enzyme domain that is activated by cytosolic calmodulin and catalyzes unregulated conversion of cellular ATP into cyclic AMP (cAMP), a key second messenger subverting bactericidal activities of phagocytes. In parallel, the hemolysin (Hly) moiety of CyaA forms cation-selective hemolytic pores that permeabilize target cell membranes. We constructed the first mutant secreting a CyaA toxin having an intact capacity to deliver the AC enzyme into CD11b-expressing (CD11b) host phagocytes but impaired in formation of cell-permeabilizing pores and defective in cAMP elevation in CD11b cells. The nonhemolytic AC Hly bacteria inhibited the antigen-presenting capacities of coincubated mouse dendritic cells and skewed their Toll-like receptor (TLR)-triggered maturation toward a tolerogenic phenotype. The AC Hly mutant also infected mouse lungs as efficiently as the parental AC Hly strain. Hence, elevation of cAMP in CD11b cells and/or the pore-forming capacity of CyaA were not required for infection of mouse airways. The latter activities were, however, involved in bacterial penetration across the epithelial layer, enhanced neutrophil influx into lung parenchyma during sublethal infections, and the exacerbated lung pathology and lethality of infections at higher inoculation doses (>10 CFU/mouse). The pore-forming activity of CyaA further synergized with the cAMP-elevating activity in downregulation of major histocompatibility complex class II (MHC-II) molecules on infiltrating myeloid cells, likely contributing to immune subversion of host defenses by the whooping cough agent.