Signaling by Fyn-ADAP via the Carma1–Bcl-10–MAP3K7 signalosome exclusively regulates inflammatory cytokine production in NK cells

Rajasekaran, Kamalakannan; Kumar, Pawan; Schuldt, Kristina; Peterson, Erik; Vanhaesebroeck, Bart; Dixit, Vishva M.; Thakar, Monica S.; Malarkannan, Subramaniam

doi:10.1038/ni.2708

Cited by 83 publications

(102 citation statements)

References 50 publications

(72 reference statements)

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“…Triggering of activating NK receptors induces actin polymerization, phosphatidylinositol-3-OH kinase activation and phosphorylation of MEK and ERK, ultimately promoting NK-cell cytotoxicity 14 . We analyzed NK-cell degranulation upon engagement of CD16, NKp30, NKp46 (all of which use CD3ζ and FcεRIγ), or NKG2D (which recruits the DAP10 adaptor), and observed severely impaired degranulation in P1 (Fig.3B), and moderately impaired in P2, likely corresponding to residual amounts of DOCK2 protein in P2’s hematopoietic cells (Fig.S4A).…”

Section: Resultsmentioning

confidence: 99%

Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections

Dobbs¹,

et al. 2015

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Background Combined immunodeficiencies (CIDs) denote inborn errors of T-cell immunity with T cells present but quantitatively or functionally deficient. Impaired humoral immunity, either due to a primary B cell defect or secondary to the T-cell defect, is also frequent. Consequently, patients with CID display severe infections and/or autoimmunity. The specific molecular, cellular, and clinical features of many types of CID remain unknown. Methods We performed genetic and cellular immunological studies in five unrelated children who shared a history of early-onset invasive bacterial and viral infections, with lymphopenia and defective T-, B-, and NK-cell responses. Two patients died early in childhood, whereas the other three underwent allogeneic hematopoietic stem cell transplantation with normalization of T cell function and clinical improvement. Results We identified bi-allelic mutations in the Dedicator Of Cytokinesis 2 (DOCK2) gene in these five patients. RAC1 activation was impaired in T cells. Chemokine-induced migration and actin polymerization were defective in T, B, and NK cells. NK-cell degranulation was also affected. The production of interferon (IFN)-α and -λ by peripheral blood mononuclear cells (PBMCs) was diminished following virus infection. Moreover, in DOCK2-deficient fibroblasts, virus replication was increased and there was enhanced virus-induced cell death, which could be normalized by treatment with IFN-α2β or upon expression of wild-type DOCK2. Conclusions Autosomal recessive DOCK2 deficiency is a Mendelian disorder with pleiotropic defects of hematopoietic and non-hematopoietic immunity. Children with clinical features of CID, especially in the presence of early-onset, invasive infections may have this condition.

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Section: Resultsmentioning

confidence: 99%

Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections

Dobbs¹,

et al. 2015

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“…It is well known that cytokine secretion and cytotoxicity can be uncoupled in target-stimulated NK cells 38 . Since the loss of FcεRIγ/Syk module has been associated to an increased IFNγ producing potential, 39 we explored the ability of anti-CD20-experienced NK cells to secrete IFNγ.…”

Section: Resultsmentioning

confidence: 99%

Obinutuzumab-mediated high-affinity ligation of FcγRIIIA/CD16 primes NK cells for IFNγ production

et al. 2017

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Natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), based on the recognition of IgG-opsonized targets by the low-affinity receptor for IgG FcγRIIIA/CD16, represents one of the main mechanisms by which therapeutic antibodies (mAbs) mediate their antitumor effects. Besides ADCC, CD16 ligation also results in cytokine production, in particular, NK-derived IFNγ is endowed with a well-recognized role in the shaping of adaptive immune responses.Obinutuzumab is a glycoengineered anti-CD20 mAb with a modified crystallizable fragment (Fc) domain designed to increase the affinity for CD16 and consequently the killing of mAb-opsonized targets. However, the impact of CD16 ligation in optimized affinity conditions on NK functional program is not completely understood.Herein, we demonstrate that the interaction of NK cells with obinutuzumab-opsonized cells results in enhanced IFNγ production as compared with parental non-glycoengineered mAb or the reference molecule rituximab. We observed that affinity ligation conditions strictly correlate with the ability to induce CD16 down-modulation and lysosomal targeting of receptor-associated signaling elements. Indeed, a preferential degradation of FcεRIγ chain and Syk kinase was observed upon obinutuzumab stimulation independently from CD16-V158F polymorphism. Although the downregulation of FcεRIγ/Syk module leads to the impairment of cytotoxic function induced by NKp46 and NKp30 receptors, obinutuzumab-experienced cells exhibit an increased ability to produce IFNγ in response to different stimuli.These data highlight a relationship between CD16 aggregation conditions and the ability to promote a degradative pathway of CD16-coupled signaling elements associated to the shift of NK functional program.

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“…Although ADAP is important for optimal interactions between naïve T cells and Ag-laden APCs both in vitro and in vivo (14, 19, 21), there have been conflicting reports on the role of ADAP in killing of target cells by effector CD8 T cells (24, 25) or NK cells (20, 55). One study reported enhanced cytolytic function of ADAP −/− tumor-specific CTLs in vitro and in vivo (23), while another study reported that CD8 CTLs lacking ADAP exhibited normal cytotoxicity in response to an allogenic graft (25).…”

Section: Discussionmentioning

confidence: 99%

“…The downstream effects of TCR-inducible interactions of ADAP with caspase recruitment domain (CARD) membrane-associated guanylate kinase (MAGUK) protein 1 (CARMA-1) and, transforming growth factor-β (TGF-β)-activated protein kinase (TAK-1) promote T cell entry into the cell cycle (9, 15–17). The ADAP-CARMA-1-TAK-1 signalosome is also required for cytokine and chemokine production by NK cells after NKG2D or CD137 stimulation (20). …”

Section: Introductionmentioning

confidence: 99%

Adhesion- and Degranulation-Promoting Adapter Protein Promotes CD8 T Cell Differentiation and Resident Memory Formation and Function during an Acute Infection

Fiege

Beura

Burbach

et al. 2016

The Journal of Immunology

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During acute infections, naïve antigen-specific CD8 T cells are activated and differentiate into effector T cells, the majority of which undergo contraction after pathogen clearance. A small population of CD8 T cells persists as memory to protect against future infections. We investigated the role of adhesion and degranulation promoting adapter protein (ADAP) in promoting CD8 T cell responses to a systemic infection. Naïve antigen-specific CD8 T cells lacking ADAP exhibited a modest expansion defect early after Listeria monocytogenes or vesicular stomatitis virus infection but comparable cytolytic function at the peak of response. However, reduced numbers of ADAP-deficient CD8 T cells were present in the spleen after the peak of the response. ADAP deficiency resulted in a greater frequency of CD127+ CD8 memory precursors in secondary lymphoid organs during the contraction phase. Reduced numbers of ADAP-deficient KLRG1− resident memory CD8 T cell (TRM) precursors were present in a variety of non-lymphoid tissues at the peak of the immune response, and consequently the total numbers of ADAP-deficient TRM were reduced at memory time points. TRM cells that did form in the absence of ADAP were defective in effector molecule expression. ADAP-deficient TRM cells exhibited impaired effector function after Ag re-challenge, correlating with defects in their ability to form T:APC conjugates. However, ADAP-deficient TRM cells responded to TGFβ signals and recruited circulating memory CD8 T cells. Thus, ADAP regulates CD8 T cell differentiation events following acute pathogen challenge that are critical for the formation and select functions of TRM cells in non-lymphoid tissues.

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Signaling by Fyn-ADAP via the Carma1–Bcl-10–MAP3K7 signalosome exclusively regulates inflammatory cytokine production in NK cells

Cited by 83 publications

References 50 publications

Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections

Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections

Obinutuzumab-mediated high-affinity ligation of FcγRIIIA/CD16 primes NK cells for IFNγ production

Adhesion- and Degranulation-Promoting Adapter Protein Promotes CD8 T Cell Differentiation and Resident Memory Formation and Function during an Acute Infection

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