Inherited CD70 deficiency in humans reveals a critical role for the CD70–CD27 pathway in immunity to Epstein-Barr virus infection

Izawa, Kazushi; Martin, Emmanuel; Soudais, Claire; Bruneau, Julie; Boutboul, David; Rodriguez, Rémy; Lenoir, Christelle; Hislop, Andrew D.; Besson, Caroline; Touzot, Fabien; Pïcard, Capucine; Callebaut, Isabelle; Villartay, Jean‐Pierre de; Moshous, Despina; Fischer, Alain; Latour, Sylvain

doi:10.1084/jem.20160784

Cited by 137 publications

(145 citation statements)

References 48 publications

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“…Studies of larger cohorts are required to fully characterize EBNA-1-associated MM, and to determine whether these patients may carry specific genetic alterations. In particular, the high incidence of males in the EBNA-1-associated MM group might indicate hereditary, X-linked susceptibility to an abnormal immune response to EBV infection and EBV-associated MGUS and myeloma, as recently reported for certain cases of B cell lymphomas (32)(33)(34).…”

Section: Discussionmentioning

confidence: 62%

Monoclonal IgG in MGUS and multiple myeloma targets infectious pathogens

Bosseboeuf¹,

Feron²,

Tallet³

et al. 2017

JCI Insight

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International audienceSubsets of mature B cell neoplasms are linked to infection with intracellular pathogens such as Epstein-Barr virus (EBV), hepatitis C virus (HCV), or Helicobacter pylori. However, the association between infection and the immunoglobulin-secreting (Ig-secreting) B proliferative disorders remains largely unresolved. We investigated whether the monoclonal IgG (mc IgG) produced by patients diagnosed with monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM) targets infectious pathogens. Antigen specificity of purified mc IgG from a large patient cohort (n = 244) was determined using a multiplex infectious-antigen array (MIAA), which screens for reactivity to purified antigens or lysates from 9 pathogens. Purified mc IgG from 23.4% of patients (57 of 244) specifically recognized 1 pathogen in the MIAA. EBV was the most frequent target (15.6%), with 36 of 38 mc IgGs recognizing EBV nuclear antigen-1 (EBNA-1). MM patients with EBNA-1-specific mc IgG (14.0%) showed substantially greater bone marrow plasma cell infiltration and higher β2-microglobulin and inflammation/infection-linked cytokine levels compared with other smoldering myeloma/MM patients. Five other pathogens were the targets of mc IgG: herpes virus simplex-1 (2.9%), varicella zoster virus (1.6%), cytomegalovirus (0.8%), hepatitis C virus (1.2%), and H. pylori (1.2%). We conclude that a dysregulated immune response to infection may underlie disease onset and/or progression of MGUS and MM for subsets of patients

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Section: Discussionmentioning

confidence: 62%

Monoclonal IgG in MGUS and multiple myeloma targets infectious pathogens

Bosseboeuf¹,

Feron²,

Tallet³

et al. 2017

JCI Insight

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“…Several primary immune deficiencies caused by mutations in SH2D1A , CTPS1, MAGT1, ITK, CD27, and CD70 are characterized by a high susceptibility to develop recurrent EBV‐driven B‐cell lymphoproliferative disorders (LPD), although these patients can also develop other infections (Veillette et al , ; Cohen, ; Tangye et al , ). The particular importance of T‐cell proliferation in anti‐EBV immunity is notably exemplified by the CTPS1 and CD70 deficiencies (Martin et al , ; Abolhassani et al , ; Izawa et al , ). CTPS1 is required for the de novo synthesis of the CTP nucleotide, a precursor of the metabolism of nucleic acids.…”

Section: Introductionmentioning

confidence: 99%

Loss of RASGRP 1 in humans impairs T‐cell expansion leading to Epstein‐Barr virus susceptibility

et al. 2018

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Inherited CTPS1, CD27, and CD70 deficiencies in humans have revealed key factors of T‐lymphocyte expansion, a critical prerequisite for an efficient immunity to Epstein–Barr virus (EBV) infection. RASGRP1 is a T‐lymphocyte‐specific nucleotide exchange factor known to activate the pathway of MAP kinases (MAPK). A deleterious homozygous mutation in RASGRP1 leading to the loss RASGRP1 expression was identified in two siblings who both developed a persistent EBV infection leading to Hodgkin lymphoma. RASGRP1‐deficient T cells exhibited defective MAPK activation and impaired proliferation that was restored by expression of wild‐type RASGRP1. Similar defects were observed in T cells from healthy individuals when RASGRP1 was downregulated. RASGRP1‐deficient T cells also exhibited decreased CD27‐dependent proliferation toward CD70‐expressing EBV‐transformed B cells, a crucial pathway required for expansion of antigen‐specific T cells during anti‐EBV immunity. Furthermore, RASGRP1‐deficient T cells failed to upregulate CTPS1, an important enzyme involved in DNA synthesis. These results show that RASGRP1 deficiency leads to susceptibility to EBV infection and demonstrate the key role of RASGRP1 at the crossroad of pathways required for the expansion of activated T lymphocytes.

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“…CD70-CD27 interaction provides a potent second signal for CD4 T cell-dependent and -independent CD8 T cell priming, effector differentiation, and memory development in virus clearance or tumor rejection (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Human CD27 or CD70 deficiency due to genetic mutations resulted in persistent symptomatic EBV infection and EBV-associated lymphoproliferative disorders, including lethal lymphoma (26)(27)(28)(29)(30). In contrast, triggering CD27 persistently, such as by constitutively expressing CD70 in transgenic mouse models, resulted in a progressive and ultimately lethal deficiency in T cells, NK cells, and B cells due to direct exhaustion and activationinduced cell death (AICD) or IFN-g-mediated indirect depletion (31)(32)(33)(34).…”

mentioning

confidence: 99%

CD27-Mediated Regulatory T Cell Depletion and Effector T Cell Costimulation Both Contribute to Antitumor Efficacy

Wasiuk

Testa

Weidlick

et al. 2017

The Journal of Immunology

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CD27, a member of the TNFR superfamily, is constitutively expressed in most T cells and plays crucial roles in T cell effector functions. The costimulation and antitumor activity of CD27 agonistic Abs have been well documented in mouse models. Clinical testing of a human IgG1 anti-CD27 Ab, varlilumab (clone 1F5), is ongoing in cancer patients. In this study, we set out to further understand CD27 as an immunomodulatory target and to address the mechanism of antitumor efficacy using different IgG isotypes of 1F5 in human CD27-transgenic mice. 1F5mIgG1, the only isotype engaging inhibitory FcγRIIB expressed in B cells, elicited the most potent and broad immune response, but terminal differentiation, exhaustion, and apoptosis in the activated effector T cells were inevitable. Accordingly, this isotype was the most effective in eradicating BCL1 lymphoma but had limited efficacy in s.c. tumors. Conversely, 1F5mIgG2a, which interacts with cells expressing activating FcγRs, led to moderate immune activation, as well as to prominent reduction in the number and suppressive activity of regulatory T cells. These combined mechanisms imparted potent antitumor activity to 1F5mIgG2a, particularly against the s.c. tumors. 1F5hIgG1, varlilumab, showed balanced agonistic activity that was prominent at lower doses and depleting activity that was greater at higher doses. 1F5hIgG1 had good antitumor activity in all tumor models tested. Thus, both agonist and depleting properties contribute to the antitumor efficacy of CD27-targeted immunotherapy, and modulation of these activities in patients may be achieved by varying the dose and regimen.

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Inherited CD70 deficiency in humans reveals a critical role for the CD70–CD27 pathway in immunity to Epstein-Barr virus infection

Abstract: Izawa et al. identify the first patient with CD70 deficiency suffering from recurrent EBV-induced B cell proliferations including Hodgkin’s lymphoma. Expression of CD70 on B cells is necessary to induce proliferation of EBV-specific T cells.

Cited by 137 publications

References 48 publications

Monoclonal IgG in MGUS and multiple myeloma targets infectious pathogens

Monoclonal IgG in MGUS and multiple myeloma targets infectious pathogens

Loss of RASGRP 1 in humans impairs T‐cell expansion leading to Epstein‐Barr virus susceptibility

CD27-Mediated Regulatory T Cell Depletion and Effector T Cell Costimulation Both Contribute to Antitumor Efficacy

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