Natural killer cell hyporesponsiveness and impaired development in a CD247-deficient patient

Valés‐Gómez, Mar; Esteso, Gloria; Aydoğmuş, Çiğdem; Blázquez-Moreno, Alfonso; Marín, Ana V.; Briones, Alejandro C.; Garcillán, Beatriz; García‐Cuesta, Eva M.; Cobo, Sheila López; Haskoloğlu, Şule; Moraru, Manuela; Çipe, Funda; Dobbs, Kerry; Doğu, Figen; Parolini, Silvia; Notarangelo, Luigi D.; Vilches, Carlos; Recio, María J.; Regueiro, José R.; İkincioğulları, Aydan; Reyburn, Hugh

doi:10.1016/j.jaci.2015.07.051

Cited by 13 publications

(16 citation statements)

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“…It has previously been reported that cell surface expression of the CD16A receptor depends on a noncovalent association with the signaling dimers FceR1γ and/or CD247 (2)(3)(4). Ex vivo analysis of CD16A cell surface expression on primary human NK cells deficient in either FceR1γ or CD247 has suggested that CD16A does not discriminate between these adaptor molecules (15), and we confirmed these data in vitro when fibroblasts were transfected with CD16A alone or in combination with either FceR1γ or CD247 adaptor molecules. Only small amounts of CD16A protein, which correspond to an immature (EndoH-sensitive) species, were detected in cells transfected with the receptor construct alone (Fig.…”

Section: Cd16asupporting

confidence: 85%

“…It therefore seems likely that the major factors influencing whether CD16A associates with CD247 or FceR1γ are related to the relative levels of expression of the different adaptors and possible competition from other receptors that also bind CD247 and FceR1γ. For example, a population of terminally differentiated human NK cells lose expression of FceR1γ (31), and, in these cells, CD16A associates exclusively with CD247 (15). In contrast, the majority of circulating human NK cells express both FceR1γ and CD247, but they also express multiple NK receptors that associate with these adaptor molecules.…”

Section: Discussionmentioning

confidence: 99%

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Transmembrane features governing Fc receptor CD16A assembly with CD16A signaling adaptor molecules

Blázquez-Moreno

Park

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Many activating immunoreceptors associate with signaling adaptor molecules like FceR1γ or CD247. FceR1γ and CD247 share high sequence homology and form disulphide-linked homodimers that contain a pair of acidic aspartic acid residues in their transmembrane (TM) domains that mediate assembly, via interaction with an arginine residue at a similar register to these aspartic acids, with the activating immunoreceptors. However, this model cannot hold true for receptors like CD16A, whose TM domains do not contain basic residues. We have carried out an extensive site-directed mutagenesis analysis of the CD16A receptor complex and now report that the association of receptor with the signaling adaptor depends on a network of polar and aromatic residues along the length of the TM domain. Molecular modeling indicates that CD16A TM residues F 202 , D 205, and T 206 form the core of the membrane-embedded trimeric interface by establishing highly favorable contacts to the signaling modules through rearrangement of a hydrogen bond network previously identified in the CD247 TM dimer solution NMR structure. Strikingly, the amino acid D 205 also regulates the turnover and surface expression of CD16A in the absence of FceR1γ or CD247. Modeling studies indicate that similar features underlie the association of other activating immune receptors, including CD64 and FceR1α, with signaling adaptor molecules, and we confirm experimentally that equivalent F, D, and T residues in the TM domain of FceR1α markedly influence the biology of this receptor and its association with FceR1γ. dim natural killer (NK) cells, subsets of monocytes, dendritic cells, and rare T cells. FcγRIIIB (CD16B) is encoded by a distinct gene and is preferentially expressed by neutrophils (1). CD16B is a GPI-anchored glycoprotein whereas CD16A is a type 1 membrane glycoprotein with a single transmembrane (TM) domain and a short cytoplasmic tail whose expression at the cell surface depends on association with the signaling adaptor molecules CD247 (TCRζ) and/or FceR1γ (1-4). First discovered as components of the TCR:CD3 complex and the high affinity receptor for IgE, respectively (5-7), CD247 and FceR1γ are integral membrane proteins that have subsequently been found to be obligate signaling adaptors for many immunoreceptors in different cell types. Both adaptors have very short extracellular domains and cytoplasmic tails that contain immunoreceptor tyrosinebased activating motifs (ITAMs) for signal transduction. Moreover, both CD247 and FceR1γ form dimers in the endoplasmic reticulum (ER) that are stabilized by a disulphide bond at the junction between the extracellular and TM domains so that, at the cell surface, CD247 and FceR1γ in complex with their client receptors are dimeric. In general, the receptors known to associate with CD247 and FceR1γ have short intracellular tails and thus are completely dependent on these adaptors to signal, although phosphorylation of a protein kinase C (PKC) motif in the cytoplasmic tail of CD16A can modulate the outcome of receptor ...

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Section: Cd16asupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Transmembrane features governing Fc receptor CD16A assembly with CD16A signaling adaptor molecules

Blázquez-Moreno

Park

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…To our knowledge, only two of these genes have been suggested to play a role in allergic disease through functional studies: USF1 80 and STARD3 81 . However, many have a known function ( Supplementary Table 10 ) that is directly relevant to allergic disease pathophysiology, such as F11R 82 , 83 , MICB 84 , CD247 85 , 86 , PGAP3 87 , AAGAB , 88 CAMK4 89 and PEX14 90 . In summary, of the 49 likely target genes of published asthma risk variants, only 16 were previously implicated by functional studies in disease pathophysiology.…”

Section: Do Any Of the Likely Target Genes Represent Potential New Plmentioning

confidence: 99%

Lessons from ten years of genome‐wide association studies of asthma

2017

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Twenty-five genome-wide association studies (GWAS) of asthma were published between 2007 and 2016, the largest with a sample size of 157242 individuals. Across these studies, 39 genetic variants in low linkage disequilibrium (LD) with each other were reported to associate with disease risk at a significance threshold of P<5 × 10−8, including 31 in populations of European ancestry. Results from analyses of the UK Biobank data (n=380 503) indicate that at least 28 of the 31 associations reported in Europeans represent true-positive findings, collectively explaining 2.5% of the variation in disease liability (median of 0.06% per variant). We identified 49 transcripts as likely target genes of the published asthma risk variants, mostly based on LD with expression quantitative trait loci (eQTL). Of these genes, 16 were previously implicated in disease pathophysiology by functional studies, including TSLP, TNFSF4, ADORA1, CHIT1 and USF1. In contrast, at present, there is limited or no functional evidence directly implicating the remaining 33 likely target genes in asthma pathophysiology. Some of these genes have a known function that is relevant to allergic disease, including F11R, CD247, PGAP3, AAGAB, CAMK4 and PEX14, and so could be prioritized for functional follow-up. We conclude by highlighting three areas of research that are essential to help translate GWAS findings into clinical research or practice, namely validation of target gene predictions, understanding target gene function and their role in disease pathophysiology and genomics-guided prioritization of targets for drug development.

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“…1 Regarding B cells, the role of NF-kB1 was underlined in a murine nf-kb1 knockout model in which peripheral B cells showed defective maturation, defective isotype switching, and impaired humoral immune responses. [1][2][3] A similar, although more pronounced, immunologic phenotype was observed in the nf-kb2 knockout mice, with defective secondary lymphoid organ development and impaired B-cell development both in early (bone marrow) and in late (periphery) stages with defective humoral responses both to T-dependent and to T-independent antigens. 1 The role of NF-kB2 in human B-cell development was recently defined in patients carrying monoallelic mutations in NF-kB2, leading to common variable immunodeficiency (CVID)-like disease with autoimmunity and defects in late stages of peripheral B-cell maturation.…”

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confidence: 57%

Primary T-cell immunodeficiency with functional revertant somatic mosaicism in CD247

Marín

Jiménez-Reinoso

Briones

et al. 2017

Journal of Allergy and Clinical Immunology

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Natural killer cell hyporesponsiveness and impaired development in a CD247-deficient patient

Abstract: The agencies that provided financial support for the conduct of the research and preparation of the article played no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report, or in the decision to submit the article for publication.

Cited by 13 publications

References 13 publications

Transmembrane features governing Fc receptor CD16A assembly with CD16A signaling adaptor molecules

Transmembrane features governing Fc receptor CD16A assembly with CD16A signaling adaptor molecules

Lessons from ten years of genome‐wide association studies of asthma

Primary T-cell immunodeficiency with functional revertant somatic mosaicism in CD247

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