Functional expression of CD137 (4-1BB) on T helper follicular cells

Alfaro, Carlos; Echeveste, José; Rodríguez-Ruiz, María E.; Solórzano, José Luis; Perez-Gracia, José Luis; Idoate, Miguel A.; López-Picazo, José M.; Sánchez-Paulete, Alfonso R.; Labiano, Sara; Rouzaut, Ana; Oñate, Carmen; Aznar, Ángela; Lozano, Marı́a D.; Melero, Ignacio

doi:10.1080/2162402x.2015.1054597

Cited by 18 publications

(11 citation statements)

References 31 publications

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“…4-1BB (CD137 or TNFRSF9) is highly expressed on human T FH cells ( 110 ). However, 4-1bb −/− mice show no impairment of IgG production following VSV infection ( 111 ).…”

Section: Molecular Interactions In T Fh Differentimentioning

confidence: 99%

Role of TRAFs in Signaling Pathways Controlling T Follicular Helper Cell Differentiation and T Cell-Dependent Antibody Responses

Pedros

Kong

2018

Front. Immunol.

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Follicular helper T (TFH) cells represent a highly specialized CD4+ T cell subpopulation that supports the generation of germinal centers (GC) and provides B cells with critical signals promoting antibody class switching, generation of high affinity antibodies, and memory formation. TFH cells are characterized by the expression of the chemokine receptor CXCR5, the transcription factor Bcl-6, costimulatory molecules ICOS, and PD-1, and the production of cytokine IL-21. The acquisition of a TFH phenotype is a complex and multistep process that involves signals received through engagement of the TCR along with a multitude of costimulatory molecules and cytokines receptors. Members of the Tumor necrosis factor Receptor Associated Factors (TRAF) represent one of the major classes of signaling mediators involved in the differentiation and functions of TFH cells. TRAF molecules are the canonical adaptor molecules that physically interact with members of the Tumor Necrosis Factor Receptor Superfamily (TNFRSF) and actively modulate their downstream signaling cascades through their adaptor function and/or E3 ubiquitin ligase activity. OX-40, GITR, and 4-1BB are the TRAF-dependent TNFRSF members that have been implicated in the differentiation and functions of TFH cells. On the other hand, emerging data demonstrate that TRAF proteins also participate in signaling from the TCR and CD28, which deliver critical signals leading to the differentiation of TFH cells. More intriguingly, we recently showed that the cytoplasmic tail of ICOS contains a conserved TANK-binding kinase 1 (TBK1)-binding motif that is shared with TBK1-binding TRAF proteins. The presence of this TRAF-mimicking signaling module downstream of ICOS is required to mediate the maturation step during TFH differentiation. In addition, JAK-STAT pathways emanating from IL-2, IL-6, IL-21, and IL-27 cytokine receptors affect TFH development, and crosstalk between TRAF-mediated pathways and the JAK-STAT pathways can contribute to generate integrated signals required to drive and sustain TFH differentiation. In this review, we will introduce the molecular interactions and the major signaling pathways controlling the differentiation of TFH cells. In each case, we will highlight the contributions of TRAF proteins to these signaling pathways. Finally, we will discuss the role of individual TRAF proteins in the regulation of T cell-dependent humoral responses.

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“…4-1BB (CD137 or TNFRSF9) is highly expressed on human T FH cells ( 110 ). However, 4-1bb −/− mice show no impairment of IgG production following VSV infection ( 111 ).…”

Section: Molecular Interactions In T Fh Differentimentioning

confidence: 99%

Role of TRAFs in Signaling Pathways Controlling T Follicular Helper Cell Differentiation and T Cell-Dependent Antibody Responses

Pedros

Kong

2018

Front. Immunol.

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“…Indeed, treatment of mice with 4-1BB-agonistic mAbs was found to induce tumor regression of established and poorly immunogenic tumors as early as 1997 12 . Since then, a large body of accumulated preclinical data has been gathered that supports the induction of 4-1BB signaling in cancer immunotherapy, both as a single agent and in combination therapies 13 .…”

Section: Introductionmentioning

confidence: 99%

A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity

Compte¹,

et al. 2018

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The costimulation of immune cells using first-generation anti-4-1BB monoclonal antibodies (mAbs) has demonstrated anti-tumor activity in human trials. Further clinical development, however, is restricted by significant off-tumor toxicities associated with FcγR interactions. Here, we have designed an Fc-free tumor-targeted 4-1BB-agonistic trimerbody, 1D8N/CEGa1, consisting of three anti-4-1BB single-chain variable fragments and three anti-EGFR single-domain antibodies positioned in an extended hexagonal conformation around the collagen XVIII homotrimerization domain. The1D8N/CEGa1 trimerbody demonstrated high-avidity binding to 4-1BB and EGFR and a potent in vitro costimulatory capacity in the presence of EGFR. The trimerbody rapidly accumulates in EGFR-positive tumors and exhibits anti-tumor activity similar to IgG-based 4-1BB-agonistic mAbs. Importantly, treatment with 1D8N/CEGa1 does not induce systemic inflammatory cytokine production or hepatotoxicity associated with IgG-based 4-1BB agonists. These results implicate FcγR interactions in the 4-1BB-agonist-associated immune abnormalities, and promote the use of the non-canonical antibody presented in this work for safe and effective costimulatory strategies in cancer immunotherapy.

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“…In immunoreactions mediated by lymphocytes, CD3 + CD4 + and CD3 + CD8 + T cells play an important role as helper T cells [ 27 ] and cytotoxic T cells [ 28 ]. The CD3 + CD4 + T cells, especially T follicular helper (Tfh) cells, secrete interleukin-21 [ 29 ] and express CD40 ligands and other inducible costimulator such as CD137 [ 30 ] on their surface [ 31 ], to promote B cells (CD19 + ) class-switch and their differentiation into plasma cells (CD138 + ) after antigen challenge [ 32 – 34 ] (Fig. 6 ) [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

The influence of HK2 blood group antigen on human B cell activation for ABOi-KT conditions

et al. 2017

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BackgroundIt is well known that ABO blood group system incompatible kidney transplantation (ABOi-KT) is an effective strategy for end-stage renal disease. The main barrier for ABOi-KT is how to keep host B cell activation and blood group antibody titer in low levels. Moreover, the mechanism of B cell activation induced by blood group antigen was unclear in ABOi-KT.ResultsIn this study, HK2 cells were identified to express blood group B antigen when cocultured with lymphocytes of blood group A. Optical microscope observation demonstrated that HK2 cells in coculture group gradually decreased. Furthermore, flow cytometer assay identified that T cell phenotypes (CD3+, CD3+CD4+ and CD3+CD8+) had no significant change and B cell phenotypes (CD19+ and CD138+) were all significantly enhanced (3.07 and 3.02 folds) at day 4. In addition, immunoturbidimetry analysis demonstrated that blood group B antibody was significantly increased to 2.35 fold at day 4, IgG was significantly increased to 3.60 and 2.81 folds at days 4 and 8 respectively, while IgM had no significant change at the measured time points.ConclusionsTaken together, B cells were activated and secreted blood group B antibody after treatment with HK2 expressing blood group B antigen. The results of this study maybe useful for further determination of the mechanism of B cell activation after ABO incompatible kidney endothelial cells stimulation.Electronic supplementary materialThe online version of this article (10.1186/s12865-017-0233-9) contains supplementary material, which is available to authorized users.

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Functional expression of CD137 (4-1BB) on T helper follicular cells

Cited by 18 publications

References 31 publications

Role of TRAFs in Signaling Pathways Controlling T Follicular Helper Cell Differentiation and T Cell-Dependent Antibody Responses

Role of TRAFs in Signaling Pathways Controlling T Follicular Helper Cell Differentiation and T Cell-Dependent Antibody Responses

A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity

The influence of HK2 blood group antigen on human B cell activation for ABOi-KT conditions

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