This work demonstrates, that the ribonuclease Regnase-3 (Zc3h12c, MCPIP3) is important to balance the immune homeostasis in vivo. Regnase-3-deficient mice develop hypertrophic lymph nodes and exhibit shifts in diverse immune cell populations. Myeloid cells were identified to provoke the pathogenicity. Further, Regnase-3 deficiency led to enhanced systemic interferon responses in vivo and in macrophages, Regnase-3 expression was induced by a viral RNA analogue via the transcription factor IRF7.