CARD11 functions as a key signaling scaffold that controls antigen-induced lymphocyte activation during the adaptive immune response. Somatic mutations in CARD11 are frequently found in Non-Hodgkin lymphoma, and at least three classes of germline CARD11 mutations have been described as the basis for primary immunodeficiency. In this review, we summarize our current understanding of how CARD11 signals, how its activity is regulated, and how mutations bypass normal regulation to cause disease.

Type I IFNs are induced in response to viral infection in two phases of innate immune signaling. The first occurs when pathogen-associated molecular patterns (PAMPs) activate either cytosolic or membrane-bound pattern recognition receptors (PRRs). These interactions stimulate signaling pathways that eventually converge on the activation of the transcription factors IRF3, IRF7, and/or NF-B, which lead to the transcription of early type I IFN subtypes. In mice, these early subtypes consist of IFN-␤ and IFN-␣4 (2). However, in humans, it is not known exactly which type I IFN subtypes are induced early. These early subtypes are secreted from the cells and bind to the IFN receptor (IFNAR), which stimulates the phosphorylation of the receptor-associated kinases JAK1 and Tyk2 and subsequently the transcription factors STAT1 and STAT2. Serine phosphorylation of STAT proteins also occurs and is required for optimal transcriptional activity (3). These phosphorylated STATs complex with IRF9 to form the interferon-stimulated gene factor 3 (ISGF3) complex, which translocates into the nucleus to activate the transcription of hundreds of ISGs, IRF7, and additional type I IFNs to amplify the response (4-6). This positive-feedback amplification loop continues until negative regulators of IFN signaling, such as SOCS proteins and IRF2, become activated.Sendai virus (SeV) has long been used to study type I IFN regulation due to its robust ability to induce large quantities of the type I IFN subtypes (7-9). Reports studying the transcriptional regulation of the IFN-␣ subtypes in response to SeV infection have indicated that IRF3 and IRF7 play central roles (1). In these stud- Citation Zaritsky LA, Bedsaul JR, Zoon KC. 2015. Virus multiplicity of infection affects type I interferon subtype induction profiles and interferon-stimulated genes.

CARD11 is a multidomain scaffold protein required for normal activation of NF-κB, JNK, and mTOR during Ag receptor signaling. Germline CARD11 mutations cause at least three types of primary immunodeficiency including CARD11 deficiency, B cell expansion with NF-κB and T cell anergy (BENTA), and CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS). CADINS is uniquely caused by heterozygous loss-of-function CARD11 alleles that act as dominant negatives. CADINS patients present with frequent respiratory and skin infections, asthma, allergies, and atopic dermatitis. However, precisely how a heterozygous dominant negative CARD11 allele leads to the development of this CADINS-specific cluster of symptoms remains poorly understood. To address this, we generated mice expressing the CARD11 R30W allele originally identified in patients. We find that CARD11R30W/+ mice exhibit impaired signaling downstream of CARD11 that leads to defects in T, B, and NK cell function and immunodeficiency. CARD11R30W/+ mice develop elevated serum IgE levels with 50% penetrance that becomes more pronounced with age, but do not develop spontaneous atopic dermatitis. CARD11R30W/+ mice display reduced regulatory T cell numbers, but not the Th2 expansion observed in other mice with diminished CARD11 activity. Interestingly, the presence of mixed CARD11 oligomers in CARD11R30W/+ mice causes more severe signaling defects in T cells than in B cells, and specifically impacts IFN-γ production by NK cells, but not NK cell cytotoxicity. Our findings help explain the high susceptibility of CADINS patients to infection and suggest that the development of high serum IgE is not sufficient to induce overt atopic symptoms.