Classical DC (cDC) are required for efficient protective T-cell immunity. Moreover, recent data indicate that cDC also play a critical role in mediating homeostatic proliferation and maintenance of peripheral Treg. Here, we corroborate these findings by defining CD80/CD86 costimulation as an essential molecular component required for the cDC–Treg interactions. In contrast to earlier reports, the reduced Treg compartment of mice lacking cDC or selective CD80/86 expression on cDC, as such, did not render the respective animals prone to systemic lymphocyte hyperactivation or autoimmunity. Rather, we provide evidence that elevated immunoglobulin titers, as well as changes in T-cell subset prevalence and activation status are strictly associated with the nonmalignant myeloproliferative disorder triggered by the absence of cDC.