Constitutive CD27/CD70 Interaction Induces Expansion of Effector-Type T Cells and Results in IFNγ-Mediated B Cell Depletion

Arens, Ramon; Tesselaar, Kiki; Baars, Paul A.; Schijndel, G. M. W. Van; Hendriks, Jenny; Pals, Steven T.; Krimpenfort, Paul; Borst, Jannie; Oers, Marinus H. J. van; Lier, R. A. W. Van

doi:10.1016/s1074-7613(01)00236-9

Cited by 225 publications

(294 citation statements)

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“…Reduced CD27 expression has also been described for activated T cells in vitro cocultured with CD70 1 B-cell lines [27]. Moreover, previous research conducted in the same CD70-Tg mice showed downregulated CD27 expression in BM located haematopoietic progenitor cells and both splenic and peripheral lymph nodes T-cell populations [28,29]. In peripheral lymph nodes, B and T cells are www.eji-journal.eu located in the cortex and the paracortex, respectively.…”

Section: Discussionmentioning

confidence: 68%

“…The present study is the first to investigate the possible effects of continuous in vivo triggering of CD27 on NK cells. Our experimental setup was based on CD70-Tg mice, in which all B cells constitutively express CD70 [29]. The first major effect we evidenced in these mice was severe down-modulated CD27 expression on NK cells, already established at 4 wk of age.…”

Section: Discussionmentioning

confidence: 99%

“…CD70, the ligand of CD27, is a type II transmembrane protein of the TNF family transiently up-regulated on activated lymphocytes [26]. Interestingly, down-modulation of CD27 expression is witnessed in T cells upon in vitro incubation with CD70 1 B-cell lines [27] as well as in BM progenitor cells and peripheral T cells in CD70-Tg mice [28,29]. Also, progressive differentiation of naïve T cells into effector-memory T cells is evidenced in CD70-Tg mice [30].…”

Section: Introductionmentioning

confidence: 99%

“…However, when we treated CD70-Tg mice from 3 wk of age, when NK cell numbers are still normal, with blocking antimouse CD95 ligand mAb versus isotype control, NK cell numbers were not rescued after 4 wk of treatment (data not shown). Therefore, we have no evidence at present that the increased expression of CD95 on NK cells from CD70-Tg mice leads to the reduction in NK cell numbers.In CD70-Tg mice, T cells are activated through CD27-CD70 interaction inducing IFN-g secretion, which reduces normal B-cell development in BM [29]. Therefore, we addressed the role of IFN-g in the evidenced NK cell depletion.…”

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Continuous CD27 triggering in vivo strongly reduces NK cell numbers

et al. 2010

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NK cells are important mediators of the early defense. In mice, immature and mature NK (mNK) cells constitutively express the TNF receptor family member CD27; however, mNK cells eventually lose CD27 expression and become resting NK cells. Interaction of CD27 with its ligand, CD70, enhances proliferation and effector functions of NK cells. We used mice that constitutively express CD70 on B cells (CD70-Tg) to study the in vivo effects of continuous triggering of CD27 on NK cells. Continuous CD70-CD27 interaction resulted in strongly down-modulated CD27 expression on NK cells and gradually reduced absolute NK cell numbers. This reduction was most prominent in the mNK cell subpopulation and was at least partially due to increased apoptosis. Residual NK cells showed lower expression of activating Ly49 receptors and normal (liver) or decreased (spleen) IFN-c production. Nevertheless, NK cells from CD70-Tg mice displayed higher YAC-1 killing capacities. CD70-Tg NK cells exhibited up-regulated expression of NKG2D, which is in accordance with the increased YAC-1 lysis, as this is mainly NKG2D-dependent. Taken together, this study is the first to demonstrate that continuous CD70 triggering of CD27 on NK cells in vivo results in a severe reduction of NK cells. On a single cell basis, however, residual NK cells display enhanced cytotoxicity.Key words: CD70-Tg mice . Cytotoxicity . Differentiation Supporting Information available online Introduction NK cells are large granular lymphocytes of the innate immune system that play a crucial role in the early host defense [1,2]. Upon activation, they directly eliminate target cells through exocytosis of perforin-and granzyme-containing granules, or by Fas ligand (CD178) or TRAIL pathways [3][4][5][6][7]. NK cells also produce cytokines and chemokines, which enable them to recruit non-specific haematopoetic cells, activate dendritic cells and prime adaptive lymphocytes [8][9][10][11]. As such, NK cells bridge between innate and adaptive immunity. The functional behaviour of NK cells is regulated by the engagement of a broad array of activating and inhibitory cell membrane receptors (reviewed in Lanier [12]).The BM is considered to be the main site for NK cell development [13][14][15][16]. Here, multipotent haematopoietic precursors generate NK cell precursors (NKP). Murine NKP are lineage(lin) À CD122 1 NK1.1 À CD49b À . NKP differentiate into immature NK (iNK) cells, which exhibit a lin À CD122 1 NK1. [20,21]. Interestingly, Hayakawa and Smyth [22]showed that within the TCR b À NK1.1 1 gated NK cell pool there is a CD11b low subpopulation, including both iNK and early mNK cells, which is homogenously CD27 high (referred to as subset 1), whereas the CD11b high population of late mNK cells consists of two functionally distinct subsets: i.e. CD27 high (referred to as subset 2) and CD27 low (referred to as subset 3). NK cells from subset 1 are the first NK cell population detected after BM transplantation and they give rise to subset 2 after adoptive transfer. Subset 2 consists of fu...

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Continuous CD27 triggering in vivo strongly reduces NK cell numbers

et al. 2010

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“…CD40 and/or Toll‐like receptor stimulation for instance lead to CD70 expression on DCs,19, 20, 21 thereby enabling CD8 T‐cell responses, which, to a certain extent, can be CD4 T‐cell help independent 19, 22. The necessity for a tight control of CD70 expression has been shown by the loss of B cells and antibody responses upon continuous CD27 activation 23, 24. CD70 overexpressing B cells, on the other hand, augmented the generation of effector CD8 T cells in response to influenza virus infection and tumour challenge 25…”

Section: Introductionmentioning

confidence: 99%

CD70 encoded by modified vaccinia virus Ankara enhances CD8 T‐cell‐dependent protective immunity in MHC class II‐deficient mice

et al. 2018

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SummaryThe immunological outcome of infections and vaccinations is largely determined during the initial first days in which antigen‐presenting cells instruct T cells to expand and differentiate into effector and memory cells. Besides the essential stimulation of the T‐cell receptor complex a plethora of co‐stimulatory signals not only ensures a proper T‐cell activation but also instils phenotypic and functional characteristics in the T cells appropriate to fight off the invading pathogen. The tumour necrosis factor receptor/ligand pair CD27/CD70 gained a lot of attention because of its key role in regulating T‐cell activation, survival, differentiation and maintenance, especially in the course of viral infections and cancer. We sought to investigate the role of CD70 co‐stimulation for immune responses induced by the vaccine vector modified vaccinia virus Ankara–Bavarian Nordic® (MVA‐BN ®). Short‐term blockade of CD70 diminished systemic CD8 T‐cell effector and memory responses in mice. The dependence on CD70 became even more apparent in the lungs of MHC class II‐deficient mice. Importantly, genetically encoded CD70 in MVA‐BN ® not only increased CD8 T‐cell responses in wild‐type mice but also substituted for CD4 T‐cell help. MHC class II‐deficient mice that were immunized with recombinant MVA‐CD70 were fully protected against a lethal virus infection, whereas MVA‐BN ®‐immunized mice failed to control the virus. These data are in line with CD70 playing an important role for vaccine‐induced CD8 T‐cell responses and prove the potency of integrating co‐stimulatory molecules into the MVA‐BN ® backbone.

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Pharmacokinetic characterization of BMS‐936561, an anti‐CD70 antibody‐drug conjugate, in preclinical animal species and prediction of its pharmacokinetics in humans

Wang

Rangan

Sung

et al. 2015

Biopharm & Drug Disp

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CD70 is a tumor necrosis factor (TNF)-like type II integral membrane protein that is transiently expressed on activated T- and B-lymphocytes. Aberrant expression of CD70 was identified in both solid tumors and haematologic malignancies. BMS-936561 (αCD70_MED-A) is an antibody-drug conjugate composed of a fully human anti-CD70 monoclonal antibody (αCD70) conjugated with a duocarmycin derivative, MED-A, through a maleimide-containing citrulline-valine dipeptide linker. MED-A is a carbamate prodrug that is activated by carboxylesterase to its active form, MED-B, to exert its DNA alkylation activity. In vitro serum stability studies suggested the efficiencies of hydrolyzing the carbamate-protecting group in αCD70_MED-A followed a rank order of mouse>rat > >monkey>dog~human. Pharmacokinetics of αCD70_MED-A was evaluated in mice, monkeys, and dogs after single intravenous doses. In mice, αCD70_MED-A was cleared rapidly, with no detectable exposures after 15 min following dosing. In contrast, αCD70_MED-A was much more stable in monkeys and dogs. The clearance of αCD70_MED-A in monkeys was 58 mL/d/kg, ~2-fold faster than that in dogs (31 mL/d/kg). The human PK profiles of the total αCD70 and αCD70_MED-A were predicted using allometrically scaled monkeys PK parameters of αCD70 and the carbamate hydrolysis rate constant estimated in dogs. Comparing the predicted and observed human PK from the phase I study, the dose-normalized concentration-time profiles of αCD70_MED-A and the total αCD70 were largely within the 5(th)-95(th) percentile of the predicted profiles.

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Constitutive CD27/CD70 Interaction Induces Expansion of Effector-Type T Cells and Results in IFNγ-Mediated B Cell Depletion

Cited by 225 publications

References 55 publications

Continuous CD27 triggering in vivo strongly reduces NK cell numbers

Continuous CD27 triggering in vivo strongly reduces NK cell numbers

CD70 encoded by modified vaccinia virus Ankara enhances CD8 T‐cell‐dependent protective immunity in MHC class II‐deficient mice

Pharmacokinetic characterization of BMS‐936561, an anti‐CD70 antibody‐drug conjugate, in preclinical animal species and prediction of its pharmacokinetics in humans

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