Human TLR-7-, -8-, and -9-Mediated Induction of IFN-α/β and -λ Is IRAK-4 Dependent and Redundant for Protective Immunity to Viruses

Yang, Kun; Puel, Anne; Zhang, Shenying; Eidenschenk, Céline; Ku, Cheng-Lung; Casrouge, Armanda; Picard, Capucine; von Bernuth, Horst; Senechal, Brigitte; Plancoulaine, Sabine; Al-Hajjar, Sami; Al-Ghonaium, Abdulaziz; Maródi, László; Davidson, Donald; Speert, David; Roifman, Chaim; Garty, Ben-Zion; Ozinsky, Adrian; Barrat, Franck J.; Coffman, Robert L.; Miller, Richard L.; Li, Xiaoxia; Lebon, Pierre; Rodriguez-Gallego, Carlos; Chapel, Helen; Geissmann, Frédéric; Jouanguy, Emmanuelle; Casanova, Jean-Laurent

Five TLRs are thought to play an important role in antiviral immunity, sensing viral products and inducing IFN-α/β and -λ. Surprisingly, patients with a defect of IRAK-4, a critical kinase downstream from TLRs, are resistant to common viruses. We show here that IFN-α/β and -λ induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. In contrast, IFN-α/β and -λ were induced normally by TLR-3 and TLR-4 agonists. Moreover, IFN-β and -λ were normally induced by TLR-3 agonists and viruses in IRAK-4-deficient fibroblasts. We further show that IFN-α/β and -λ production in response to 9 of 11 viruses tested was normal or weakly affected in IRAK-4-deficient blood cells. Thus, IRAK-4-deficient patients may control viral infections by TLR-3- and TLR-4-dependent and/or TLR-independent production of IFNs. The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-α/β and -λ is strictly IRAK-4 dependent and paradoxically redundant for protective immunity to most viruses in humans.