Patients with Epstein Barr virus-positive lymphomas have decreased CD4(+) T-cell responses to the viral nuclear antigen 1.
Epstein Barr virus (EBV) causes lymphomas in immune competent and, at increased frequencies, in immune compromised patients. In the presence of an intact immune system, EBV-associated lymphomas express in most cases only 3 or fewer EBV antigens at the protein level, always including the nuclear antigen 1 of EBV (EBNA1). EBNA1 is a prominent target for EBV-specific CD4(+) T cell and humoral immune responses in healthy EBV carriers. Here we demonstrate that patients with EBV-associated lymphomas, primarily Hodgkin's lymphoma, lack detectable EBNA1-specific CD4(+) T-cell responses and have slightly altered EBNA1-specific antibody titers at diagnosis. In contrast, the majority of EBV-negative lymphoma patients had detectable IFN-gamma expression and proliferation by CD4(+) T cells in response to EBNA1, and carry EBNA1-specific immunoglobulins at levels similar to healthy virus carriers. Other EBV antigens, which were not present in the tumors, were recognized in less EBV positive, than negative lymphoma patients, but detectable responses reached similar CD8(+) T cell frequencies in both cohorts. Patients with EBV-positive and -negative lymphomas did not differ in T-cell responses in influenza-specific CD4(+) T cell proliferation and in antibody titers against tetanus toxoid. These data suggest a selective loss of EBNA1-specific immune control in EBV-associated lymphoma patients, which should be targeted for immunotherapy of these malignancies.
Heller
Kevin N
KN
Laboratory of Viral Immunobiology, Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY, USA.
Arrey
Frida
F
Steinherz
Peter
P
Portlock
Carol
C
Chadburn
Amy
A
Kelly
Kara
K
Münz
Christian
C
D000293:Adolescent; D000328:Adult; D000368:Aged; D034961:Antigens, Nuclear / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology*; D049109:Cell Proliferation; D002648:Child; D016207:Cytokines / Q000032:analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D017403:In Situ Hybridization; D007371:Interferon-gamma / Q000276:immunology; D008223:Lymphoma / Q000276:immunology* / Q000821:virology*; D008297:Male; D008875:Middle Aged; D016601:RNA-Binding Proteins; D055815:Young Adult
D034961:Antigens, Nuclear; D000956:Antigens, Viral; D002352:Carrier Proteins; D016207:Cytokines; C432687:EBNA1BP2 protein, human; D016601:RNA-Binding Proteins; D007371:Interferon-gamma
Int J Cancer. 2002 May 1;99(1):93-9
11948498
J Virol. 2001 Sep;75(18):8649-59
11507210
J Clin Invest. 2001 Jan;107(1):121-30
11134187
Blood. 2007 Feb 1;109(3):1138-46
16985171
N Engl J Med. 2003 Oct 2;349(14):1324-32
14523140
Nat Rev Cancer. 2004 Oct;4(10):757-68
15510157
Blood. 2006 Oct 1;108(7):2280-9
16757686
Eur J Immunol. 1989 Jul;19(7):1311-5
2788092
Blood. 2005 Nov 1;106(9):3166-74
16014568
Nat Rev Immunol. 2003 Oct;3(10):801-12
14523386
Annu Rev Med. 2005;56:29-44
15660500
Blood. 2004 Mar 1;103(5):1755-62
14604957
J Immunol Methods. 2004 Aug;291(1-2):185-95
15345316
J Immunol. 1991 Jul 1;147(1):8-13
1711085
J Exp Med. 2000 May 15;191(10):1649-60
10811859
Blood. 2007 Aug 15;110(4):1326-9
17438085
J Virol. 2005 Apr;79(8):4896-907
15795275
J Infect Dis. 1987 Jul;156(1):26-35
3036961
PLoS Med. 2007 Mar 27;4(3):e96
17388662
J Exp Med. 2004 May 17;199(10):1301-4
15148332
J Virol. 2007 May;81(9):4766-75
17314172
J Immunol Methods. 2002 Feb 1;260(1-2):157-72
11792386
J Immunol. 2004 Jun 1;172(11):6931-7
15153512
Nat Rev Immunol. 2004 Aug;4(8):595-602
15286726
J Exp Med. 1999 Jun 21;189(12):1939-46
10377189
J Exp Med. 2006 Apr 17;203(4):805-8
16549599