Recruitment of the cytoplasmic adaptor Grb2 to surface IgG and IgE provides antigen receptor–intrinsic costimulation to class-switched B cells

Engels, Niklas; König, Lars; Heemann, Christina; Lutz, Johannes; Tsubata, Takeshi; Griep, S; Schrader, Verena; Wienands, Jürgen

doi:10.1038/ni.1764

Cited by 150 publications

(176 citation statements)

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“…It was shown that the ITT phosphorylation motif of membrane-bound IgG and IgE induces ITAMinduced signaling and B-cell proliferation. 18 The ITT-like motif has also been identified in costimulatory receptors on T and NK cells. 13 However, it is unclear how ITT-like motif induces an inhibitory signaling pathway in immunological responses.…”

Section: Discussionmentioning

confidence: 99%

“…17 A report showed that the ITT motif in the cytoplasmic regions of membrane-bound IgG and IgE initiates ITAM (immunoreceptor tyrosine-based activation motif)-induced signaling and B-cell proliferation. 18 However, how ITT-like motifs function in NK or T cells is still unclear. Here we found that TIGIT associates with Grb2 and SHIP1 mainly through its ITT-like motif to induce a negative signaling, leading to the downregulation of NK cell effector function.…”

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confidence: 99%

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Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells

et al. 2012

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Activating and inhibitory receptors control natural killer (NK) cell activity. T-cell immunoglobulin and ITIM (immunoreceptor tyrosine-based inhibition motif) domain (TIGIT) was recently identified as a new inhibitory receptor on T and NK cells that suppressed their effector functions. TIGIT harbors the immunoreceptor tail tyrosine (ITT)-like and ITIM motifs in its cytoplasmic tail. However, how its ITT-like motif functions in TIGIT-mediated negative signaling is still unclear. Here, we show that TIGIT/PVR (poliovirus receptor) engagement disrupts granule polarization leading to loss of killing activity of NK cells. The ITT-like motif of TIGIT has a major role in its negative signaling. After TIGIT/PVR ligation, the ITT-like motif is phosphorylated at Tyr225 and binds to cytosolic adapter Grb2, which can recruit SHIP1 to prematurely terminate phosphatidylinositol 3-kinase (PI3K) and MAPK signaling, leading to downregulation of NK cell function. In support of this, Tyr225 or Asn227 mutation leads to restoration of TIGIT/PVR-mediated cytotoxicity, and SHIP1 silencing can dramatically abolish TIGIT/PVR-mediated killing inhibition. Meanwhile, normal cells are kept away from their cytotoxicity. Therefore, the discrimination between 'self' normal cells and 'nonself' abnormal cells has to be precisely recognized by NK cells. [5][6][7] A very large repertoire of receptors, both activating and inhibitory, is proved to be critical in NK cell function. The best-known inhibitory receptors of NK cells are the killer-cell immunoglobulin-like receptor family, whose physical ligands are MHC-I molecules that are expressed on self normal cells to protect them from NK cell lysis. 8 Other non-MHC-I inhibitory receptors, which do not associate with MHC-I molecules, are also expressed on NK cells. 9 However, their physiological and pathological significances have not been defined yet.T-cell immunoglobulin and ITIM domain (TIGIT) was recently identified as an inhibitory receptor that is expressed mainly on NK cells, activated CD4 and CD8 T cells. 10-12 TIGIT harbors one extracellular immunoglobulin domain, a type 1 transmembrane region, and an immunoglobulin tail tyrosine (ITT)-like phosphorylation motif followed by an ITIM (immunoreceptor tyrosine-based inhibition motif) of the cytoplasmic tail. 13 The physical ligands of TIGIT were identified as the poliovirus receptor (PVR, or CD155) and the PVRL2 (Nectin2, or CD112). 10,12 TIGIT can bind to PVR of human dendritic cells to enhance interleukin 10 (IL-10) production, which inhibits T-cell activation. 10 Kuchroo et al. 14 showed that TIGIT harbors a T-cell-intrinsic inhibitory function to suppress T-cell activation.Moreover, TIGIT can inhibit NK cell cytolysis through engagement with PVR or PVRL2. 11 TIGIT-deficient mice are more susceptible to autoimmune diseases. 14,15 However, the inhibitory mechanism mediated by TIGIT has not been elucidated.TIGIT contains a classical ITIM motif, which recruits either Src homology (SH) 2 domain-containing protein tyrosine phosphatases SHP1 and SHP...

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Section: Discussionmentioning

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Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells

et al. 2012

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“…Surface γ1 HC (or μ HC with a γ1 membrane-anchoring/cytoplasmic domain) can also substitute for mIgM and support B cell development (11). The mIgG cytoplasmic tail increases extrafollicular antibody-secreting cell (ASC) formation in transgenics and was shown to mediate increased BCR signal due to specific recruitment of the Grb2 adaptor (12,13). In addition, transfection experiments showed mIgG to be less sensitive than mIgM to CD22-mediated feedback (12,14), a feature not observed in knock-in models in which Cμ was replaced by Cγ1 (15,16).…”

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Premature replacement of μ with α immunoglobulin chains impairs lymphopoiesis and mucosal homing but promotes plasma cell maturation

Duchez

Amin

Cogné

et al. 2010

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

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Sequentially along B cell differentiation, the different classes of membrane Ig heavy chains associate with the Igα/Igβ heterodimer within the B cell receptor (BCR). Whether each Ig class conveys specific signals adapted to the corresponding differentiation stage remains debated. We investigated the impact of the forced expression of an IgA-class receptor throughout murine B cell differentiation by knocking in the human Cα Ig gene in place of the Sμ region. Despite expression of a functional BCR, homozygous mutant mice showed a partial developmental blockade at the pro-B/pre-BI and large pre-BII cell stages, with decreased numbers of small pre-BII cells. Beyond this stage, peripheral B cell compartments of reduced size developed and allowed specific antibody responses, whereas mature cells showed constitutive activation and a strong commitment to plasma cell differentiation. Secreted IgA correctly assembled into polymers, associated with the murine J chain, and was transported into secretions. In heterozygous mutants, cells expressing the IgA allele competed poorly with those expressing IgM from the wild-type allele and were almost undetectable among peripheral B lymphocytes, notably in gut-associated lymphoid tissues. Our data indicate that the IgM BCR is more efficient in driving early B cell education and in mucosal site targeting, whereas the IgA BCR appears particularly suited to promoting activation and differentiation of effector plasma cells.

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“…Unlike IgM, the IgG and IgE Igs have cytoplasmic tails that participate in signal transduction, independently of, or in addition to the signals mediated by Igα and Igβ [10,11]. The functional importance of the IgG1 and IgE cytoplasmic tails was demonstrated in experiments where the gene segments encoding these structures were deleted, and a profound deficiency in the development of IgG1-or IgE-expressing memory B cells was observed [12,13].…”

Section: Introductionmentioning

confidence: 99%

The IgG1 B‐cell receptor provides survival and proliferative signals analogue to the Igα but not the Igβ co‐receptor

et al. 2016

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The function of the IgM B-cell receptor (BCR) is dependent on intact signaling of the coreceptors Igα and Igβ, both of which contain a cytoplasmic tail bearing an immunoreceptor tyrosine-based activation motif. We have previously demonstrated that the cytoplasmic tail of the IgG1 BCR can partially compensate for the loss of the signaling moiety of Igα. Here, we show that unlike Igα, Igβ signaling is indispensable for the development and function of IgG1-expressing B cells. Deletion of the cytoplasmic signaling tail of Igβ compromised the survival and proliferation not only of IgM + B cells but also of IgG1-expressing B cells. In the absence of the signaling tail of Igβ, the transcription levels of the antiapoptotic gene bcl-xl and the cell-cycle gene ccnd2 were reduced, consistent with the observed defects in survival and proliferation. These results demonstrate functional differences between Igα and Igβ in the transduction of IgG1 BCR signal.Keywords: B-cell development r BCR, Cytoplasmic tail deletion r IgG1 r Igα/β Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe B-cell antigen receptor (BCR) consists of membrane-bound immunoglobulin (Ig) and the signal-transducing Igα/Igβ heterodimer [1,2]. The cytoplasmic tails of this heterodimer contain certain tyrosine residues, which assemble into the immunoreceptor tyrosine-based activation motif (ITAM) [3], and are phosphorylated upon BCR triggering. Following phosphorylation, protein kinases and adaptor molecules are recruited to the ITAM motifs and transmit signals downstream. The cytoplasmic tails of Igα/Igβ are therefore crucial for IgM BCR signal transduction, as evidenced Correspondence: Prof. Ari Waisman e-mail: waisman@uni-mainz.de by gene targeting experiments where the cytoplasmic tails of these molecules are deleted or the ITAM motifs mutated [4][5][6]. Those transduced signals eventually determine the survival of progenitor as well as mature B cells [7][8][9].During differentiation of naïve IgM + B cells to memory cells, antigen-specific B cells switch their Ig isotype to IgG (in the mouse, -1, -2a, -2b, and -3), IgA, or IgE. Unlike IgM, the IgG and IgE Igs have cytoplasmic tails that participate in signal transduction, independently of, or in addition to the signals mediated by Igα and Igβ [10,11]. The functional importance of the IgG1 and IgE cytoplasmic tails was demonstrated in experiments where the gene segments encoding these structures were deleted, and a profound deficiency in the development of IgG1-or IgE-expressing memory B cells was observed [12,13]. Previously, to assess the physiological role of IgG1, we generated the mouse strain IgH γ1μ in which B Results Generation and characterization of the IgH γ1μ Igβ c miceTo study the role of Igβ in signaling of the IgG1 BCR, we made use of mice that allow for the conditional deletion of the cytoplasmic tail of Igβ [15]. We crossed these mice to CMV-Cre line, leading to germline deletion of the region coding for that sign...

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Recruitment of the cytoplasmic adaptor Grb2 to surface IgG and IgE provides antigen receptor–intrinsic costimulation to class-switched B cells

Cited by 150 publications

References 49 publications

Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells

Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells

Premature replacement of μ with α immunoglobulin chains impairs lymphopoiesis and mucosal homing but promotes plasma cell maturation

The IgG1 B‐cell receptor provides survival and proliferative signals analogue to the Igα but not the Igβ co‐receptor

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