Inborn errors of interferon (IFN)- mediated immunity in humans: insights into the respective roles of IFN-a/b, IFN-g, and IFN-l in host defense Summary: Interferon (IFN) was originally identified as a substance ‘interfering’ with viral replication in vitro. The first IFNs to be identified were classified as type I IFNs (IFN-a/b and related molecules), two other types have since been identified: type II IFN (IFN-g) and type III IFNs (IFN-l). Each IFN binds to one of three type-specific receptors. In the mouse model of experimental infections in vivo, IFN-a/b are essential for immunity to most viruses tested, whereas IFN-g is important for immunity to a smaller number of viruses, together with bacteria, fungi, and parasites, consistent with IFN-g acting as the ‘macrophage activating factor.’ The precise role of IFN-l remains unclear. In recent years, inborn errors affecting the production of, or the response to, IFNs have been reported in human patients, shedding light onto the function of IFNs in natura. Disorders of IFN-g production, caused by IL12B, IL12RB1, and specific NEMO mutations, or of IFN-g responses, caused by IFNGR1, IFNGR2, and dominant STAT1 mutations, confer predisposition to myco- bacterial disease in patients resistant to most viruses. By contrast, disorders of IFN-a/b and IFN-l production, caused by UNC93B1 and TLR3 mutations, confer predisposition to herpes simplex encephalitis (HSE) in otherwise healthy patients. Consistently, patients with impaired responses to IFN-a/b, IFN-g, and presumably IFN-l (carrying recessive mutations in STAT1), or with impaired responses to IFN-a/b and impaired IFN-g production (carrying mutations in TYK2), or with impaired production of IFN-a/b, IFN-g, and IFN-l (carrying specific mutations in NEMO), are vulnerable to mycobacterial and viral infections, including HSE. These experiments of nature suggest that the three types of IFNs play at least two different roles in host defense. IFN-g is essential for anti-mycobacterial immunity, whereas IFN-a/b and IFN-l are essential for anti-viral immunity. Future studies in humans aim to define the specific roles of IFN-a/b and IFN-l types and individual molecules in host defense in natura. Keywords: immunodeficiency, infectious disease, interferon Shen-Ying Zhang St´ ephanie Boisson-Dupuis Ariane Chapgier Kun Yang Jacinta Bustamante Anne Puel Capucine Picard Laurent Abel Emmanuelle Jouanguy Jean-Laurent Casanova Immunological Reviews 2008 Vol. 226: 29–40 Printed in Singapore. All rights reserved r 2008 The Authors Journal compilation r 2008 Blackwell Munksgaard Immunological Reviews 0105-2896 Authors’ addresses Shen-Ying Zhang 1,2,3 , St´ ephanie Boisson-Dupuis 1,2 , Ariane Chapgier 1,2 , Kun Yang 1,2 , Jacinta Bustamante 1,2 , Anne Puel 1,2 , Capucine Picard 1,2,4 , Laurent Abel 1,2 , Emmanuelle Jouanguy 1,2,3 , Jean-Laurent Casanova 1,2,3,5 1 Laboratory of Human Genetics of Infectious Diseases, Institut National de la Sant´ e et de la Recherche M´ edicale, U550, Paris, France, EU. 2 Paris Descartes University, Necker Medical School, Paris, France, EU. 3 French-Chinese Laboratory of Genomics and Life Science, Rui-Jin Hospital, Shanghai Jiaotong University, Shanghai, China. 4 Study Center of Primary Immunodeficiency, Necker Hospital, Paris, France, EU. 5 Pediatric Hematology Immunology Unit, Necker Hospital, Paris, France, EU. Correspondence to: Jean-Laurent Casanova Laboratory of Human Genetics of Infectious Diseases Institut National de la Sant´ e et de la Recherche M´ edicale, U550 University Paris Descartes Necker Medical School 156 rue de Vaugirard 75015 Paris, France Tel.: 133 01 40 61 56 87 Fax: 133 01 40 61 56 88 e-mail: casanova@necker.fr Acknowledgements We thank Robert D. Schreiber and Ion Gresser for guiding us into the fields of IFN-g and IFN-a/b biology, respectively. We also thank the past and present members of the Laboratory of Human Genetics of Infectious Diseases for helpful discussions, particularly those individuals involved in investigating the conditions reviewed here. We also thank the patients and their families worldwide and our collaborators. Our laboratory is supported by grants from the FSER, the BNP-Paribas Foundation, the GIS Maladies Rares, the Action Concert´ ee Incitative de Microbiologie, the March of Dimes, the Dana Foundation, the INSERM, and the ANR. Jean-Laurent Casanova is an International Scholar of the Howard Hughes Medical Institute. r 2008 The Authors  Journal compilation r 2008 Blackwell Munksgaard  Immunological Reviews 226/2008 29