Key Points

  • Blockade of CD27/CD70 interaction compromises EBV-specific immune control.

  • CD27 is particularly required for the expansion and effector function of lytic EBV antigen–specific CD8+ T cells.

Abstract

Primary immunodeficiencies in the costimulatory molecule CD27 and its ligand, CD70, predispose for pathologies of uncontrolled Epstein-Barr virus (EBV) infection in nearly all affected patients. We demonstrate that both depletion of CD27+ cells and antibody blocking of CD27 interaction with CD70 cause uncontrolled EBV infection in mice with reconstituted human immune system components. While overall CD8+ T-cell expansion and composition are unaltered after antibody blocking of CD27, only some EBV-specific CD8+ T-cell responses, exemplified by early lytic EBV antigen BMLF1-specific CD8+ T cells, are inhibited in their proliferation and killing of EBV-transformed B cells. This suggests that CD27 is not required for all CD8+ T-cell expansions and cytotoxicity but is required for a subset of CD8+ T-cell responses that protect us from EBV pathology.

REFERENCES

1.
Münz
C
.
Latency and lytic replication in Epstein–Barr virus-associated oncogenesis
.
Nat Rev Microbiol
.
2019
;
17
:
691
-
700
.
2.
Epstein
MA
,
Achong
BG
,
Barr
YM
.
Virus particles in cultured lymphoblasts from Burkitt’s lymphoma
.
Lancet
.
1964
;
283
(
7335
):
702
-
703
.
3.
Epstein
MA
,
Henle
G
,
Achong
BG
,
Barr
YM
.
Morphological and biological studies on a virus in cultured lymphoblasts from Burkitt’s lymphoma
.
J Exp Med
.
1965
;
121
(
5
):
761
-
770
.
4.
Taylor
GS
,
Long
HM
,
Brooks
JM
,
Rickinson
AB
,
Hislop
AD
.
The immunology of Epstein-Barr virus-induced disease
.
Annu Rev Immunol
.
2015
;
33
(
1
):
787
-
821
.
5.
Shannon-Lowe
C
,
Rickinson
A
.
The global landscape of EBV-associated tumors
.
Front Oncol
.
2019
;
9
:
713
.
6.
Babcock
GJ
,
Thorley-Lawson
DA
.
Tonsillar memory B cells, latently infected with Epstein-Barr virus, express the restricted pattern of latent genes previously found only in Epstein-Barr virus-associated tumors
.
Proc Natl Acad Sci USA
.
2000
;
97
(
22
):
12250
-
12255
.
7.
Cohen
JI
,
Fauci
AS
,
Varmus
H
,
Nabel
GJ
.
Epstein-Barr virus: an important vaccine target for cancer prevention
.
Sci Transl Med
.
2011
;
3
(
107
):
107fs7
.
8.
Totonchy
J
,
Cesarman
E
.
Does persistent HIV replication explain continued lymphoma incidence in the era of effective antiretroviral therapy?
Curr Opin Virol
.
2016
;
20
:
71
-
77
.
9.
McHugh
D
,
Myburgh
R
,
Caduff
N
, et al
.
EBV renders B cells susceptible to HIV-1 in humanized mice
.
Life Sci Alliance
.
2020
;
3
(
8
):
e202000640
.
10.
Latour
S
,
Fischer
A
.
Signaling pathways involved in the T-cell-mediated immunity against Epstein-Barr virus: Lessons from genetic diseases
.
Immunol Rev
.
2019
;
291
(
1
):
174
-
189
.
11.
Damania
B
,
Münz
C
.
Immunodeficiencies that predispose to pathologies by human oncogenic γ-herpesviruses
.
FEMS Microbiol Rev
.
2019
;
43
(
2
):
181
-
192
.
12.
Tangye
SG
,
Latour
S
.
Primary immunodeficiencies reveal the molecular requirements for effective host defense against EBV infection
.
Blood
.
2020
;
135
(
9
):
644
-
655
.
13.
Salzer
E
,
Daschkey
S
,
Choo
S
, et al
.
Combined immunodeficiency with life-threatening EBV-associated lymphoproliferative disorder in patients lacking functional CD27
.
Haematologica
.
2013
;
98
(
3
):
473
-
478
.
14.
van Montfrans
JM
,
Hoepelman
AI
,
Otto
S
, et al
.
CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia
.
J Allergy Clin Immunol
.
2012
;
129
(
3
):
787
-
793.e6
.
15.
Alkhairy
OK
,
Perez-Becker
R
,
Driessen
GJ
, et al
.
Novel mutations in TNFRSF7/CD27: Clinical, immunologic, and genetic characterization of human CD27 deficiency
.
J Allergy Clin Immunol
.
2015
;
136
(
3
):
703
-
712.e10
.
16.
Abolhassani
H
,
Edwards
ES
,
Ikinciogullari
A
, et al
.
Combined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency
.
J Exp Med
.
2017
;
214
(
1
):
91
-
106
.
17.
Izawa
K
,
Martin
E
,
Soudais
C
, et al
.
Inherited CD70 deficiency in humans reveals a critical role for the CD70-CD27 pathway in immunity to Epstein-Barr virus infection
.
J Exp Med
.
2017
;
214
(
1
):
73
-
89
.
18.
Ghosh
S
,
Köstel Bal
S
,
Edwards
ESJ
, et al
.
Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency
.
Blood
.
2020
;
136
(
23
):
2638
-
2655
.
19.
Münz
C
.
Humanized mouse models for Epstein Barr virus infection
.
Curr Opin Virol
.
2017
;
25
:
113
-
118
.
20.
McHugh
D
,
Caduff
N
,
Murer
A
, et al
.
Infection and immune control of human oncogenic gamma-herpesviruses in humanized mice
.
Philos Trans R Soc Lond B Biol Sci
.
2019
;
374
(
1773
):
20180296
.
21.
Chatterjee
B
,
Deng
Y
,
Holler
A
, et al
.
CD8+ T cells retain protective functions despite sustained inhibitory receptor expression during Epstein-Barr virus infection in vivo
.
PLoS Pathog
.
2019
;
15
(
5
):
e1007748
.
22.
Chijioke
O
,
Müller
A
,
Feederle
R
, et al
.
Human natural killer cells prevent infectious mononucleosis features by targeting lytic Epstein-Barr virus infection [published correction appears in Cell Rep. 2015;12(5):P901]
.
Cell Rep
.
2013
;
5
(
6
):
1489
-
1498
.
23.
Rabson
M
,
Gradoville
L
,
Heston
L
,
Miller
G
.
Non-immortalizing P3J-HR-1 Epstein-Barr virus: a deletion mutant of its transforming parent, Jijoye
.
J Virol
.
1982
;
44
(
3
):
834
-
844
.
24.
Bertrand
P
,
Maingonnat
C
,
Penther
D
, et al
.
The costimulatory molecule CD70 is regulated by distinct molecular mechanisms and is associated with overall survival in diffuse large B-cell lymphoma
.
Genes Chromosomes Cancer
.
2013
;
52
(
8
):
764
-
774
.
25.
Rowe
M
,
Rowe
DT
,
Gregory
CD
, et al
.
Differences in B cell growth phenotype reflect novel patterns of Epstein-Barr virus latent gene expression in Burkitt’s lymphoma cells
.
EMBO J
.
1987
;
6
(
9
):
2743
-
2751
.
26.
Young
LS
,
Rickinson
AB
.
Epstein-Barr virus: 40 years on
.
Nat Rev Cancer
.
2004
;
4
(
10
):
757
-
768
.
27.
Cardoso
CC
,
Auat
M
,
Santos-Pirath
IM
, et al
.
The importance of CD39, CD43, CD81, and CD95 expression for differentiating B cell lymphoma by flow cytometry
.
Cytometry B Clin Cytom
.
2018
;
94
(
3
):
451
-
458
.
28.
Antsiferova
O
,
Müller
A
,
Rämer
PC
, et al
.
Adoptive transfer of EBV specific CD8+ T cell clones can transiently control EBV infection in humanized mice
.
PLoS Pathog
.
2014
;
10
(
8
):
e1004333
.
29.
Knox
JJ
,
Cosma
GL
,
Betts
MR
,
McLane
LM
.
Characterization of T-bet and eomes in peripheral human immune cells [published correction appears in Front Immunol. 2016;7:337]
.
Front Immunol
.
2014
;
5
:
217
.
30.
Paley
MA
,
Kroy
DC
,
Odorizzi
PM
, et al
.
Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection
.
Science
.
2012
;
338
(
6111
):
1220
-
1225
.
31.
de Jong
R
,
Loenen
WA
,
Brouwer
M
, et al
.
Regulation of expression of CD27, a T cell-specific member of a novel family of membrane receptors
.
J Immunol
.
1991
;
146
(
8
):
2488
-
2494
.
32.
Jung
J
,
Choe
J
,
Li
L
,
Choi
YS
.
Regulation of CD27 expression in the course of germinal center B cell differentiation: the pivotal role of IL-10
.
Eur J Immunol
.
2000
;
30
(
8
):
2437
-
2443
.
33.
van Lier
RA
,
Borst
J
,
Vroom
TM
, et al
.
Tissue distribution and biochemical and functional properties of Tp55 (CD27), a novel T cell differentiation antigen
.
J Immunol
.
1987
;
139
(
5
):
1589
-
1596
.
34.
Pich
D
,
Mrozek-Gorska
P
,
Bouvet
M
, et al
.
First days in the life of naive human B lymphocytes infected with Epstein-Barr virus
.
MBio
.
2019
;
10
(
5
):
e01723
-
19
.
35.
Mrozek-Gorska
P
,
Buschle
A
,
Pich
D
, et al
.
Epstein-Barr virus reprograms human B lymphocytes immediately in the prelatent phase of infection
.
Proc Natl Acad Sci USA
.
2019
;
116
(
32
):
16046
-
16055
.
36.
Brooks
JM
,
Long
HM
,
Tierney
RJ
, et al
.
Early T cell recognition of B cells following Epstein-Barr virus infection: identifying potential targets for prophylactic vaccination
.
PLoS Pathog
.
2016
;
12
(
4
):
e1005549
.
37.
Winter
S
,
Martin
E
,
Boutboul
D
, et al
.
Loss of RASGRP1 in humans impairs T-cell expansion leading to Epstein-Barr virus susceptibility
.
EMBO Mol Med
.
2018
;
10
(
2
):
188
-
199
.
38.
Roose
JP
,
Mollenauer
M
,
Gupta
VA
,
Stone
J
,
Weiss
A
.
A diacylglycerol-protein kinase C-RasGRP1 pathway directs Ras activation upon antigen receptor stimulation of T cells
.
Mol Cell Biol
.
2005
;
25
(
11
):
4426
-
4441
.
39.
Cannons
JL
,
Tangye
SG
,
Schwartzberg
PL
.
SLAM family receptors and SAP adaptors in immunity
.
Annu Rev Immunol
.
2011
;
29
(
1
):
665
-
705
.
40.
Hislop
AD
,
Palendira
U
,
Leese
AM
, et al
.
Impaired Epstein-Barr virus-specific CD8+ T-cell function in X-linked lymphoproliferative disease is restricted to SLAM family-positive B-cell targets
.
Blood
.
2010
;
116
(
17
):
3249
-
3257
.
41.
Latour
S
,
Winter
S
.
Inherited immunodeficiencies with high predisposition to Epstein-Barr virus-driven lymphoproliferative diseases
.
Front Immunol
.
2018
;
9
:
1103
.
42.
Parolini
S
,
Bottino
C
,
Falco
M
, et al
.
X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells
.
J Exp Med
.
2000
;
192
(
3
):
337
-
346
.
43.
Tangye
SG
.
XLP: clinical features and molecular etiology due to mutations in SH2D1A encoding SAP
.
J Clin Immunol
.
2014
;
34
(
7
):
772
-
779
.
44.
Chijioke
O
,
Marcenaro
E
,
Moretta
A
,
Capaul
R
,
Münz
C
.
The SAP-dependent 2B4 receptor mediates CD8+ T cell dependent immune control of Epstein Barr virus infection in mice with reconstituted human immune system components
.
J Infect Dis
.
2015
;
212
(
5
):
803
-
807
.
45.
Alosaimi
MF
,
Hoenig
M
,
Jaber
F
, et al
.
Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency
.
J Allergy Clin Immunol
.
2019
;
144
(
2
):
574
-
583.e5
.
46.
Chaigne-Delalande
B
,
Li
FY
,
O’Connor
GM
, et al
.
Mg2+ regulates cytotoxic functions of NK and CD8 T cells in chronic EBV infection through NKG2D
.
Science
.
2013
;
341
(
6142
):
186
-
191
.
47.
Johnson
DB
,
McDonnell
WJ
,
Gonzalez-Ericsson
PI
, et al
.
A case report of clonal EBV-like memory CD4+ T cell activation in fatal checkpoint inhibitor-induced encephalitis
.
Nat Med
.
2019
;
25
(
8
):
1243
-
1250
.
48.
Schwab
C
,
Gabrysch
A
,
Olbrich
P
, et al
.
Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4–insufficient subjects
.
J Allergy Clin Immunol
.
2018
;
49.
Volk
V
,
Theobald
SJ
,
Danisch
S
, et al
.
PD-1 blockade aggravates Epstein-Barr virus+ post-transplant lymphoproliferative disorder in humanized mice resulting in central nervous system involvement and CD4+ T cell dysregulations
.
Front Oncol
.
2021
;
10
:
614876
.
50.
Appay
V
,
Dunbar
PR
,
Callan
M
, et al
.
Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections
.
Nat Med
.
2002
;
8
(
4
):
379
-
385
.
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