Primary human herpesvirus 8 infection generates a broadly specific CD8+ T-cell response to viral lytic cycle proteins

Blood ◽  
2001 ◽  
Vol 97 (8) ◽  
pp. 2366-2373 ◽  
Author(s):  
Qiong J. Wang ◽  
Frank J. Jenkins ◽  
Lisa P. Jacobson ◽  
Lawrence A. Kingsley ◽  
Richard D. Day ◽  
...  
Keyword(s):  
T Cell ◽  
Capsid Protein ◽  
Cell Response ◽  
Human Herpesvirus ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Lytic Cycle ◽  
Human Herpesvirus 8 ◽  
Herpesvirus 8 ◽  
Ifn Γ

Abstract Human herpesvirus 8 (HHV-8) is a recently discovered gammaherpesvirus that is the etiologic agent of Kaposi sarcoma (KS). The natural history of primary HHV-8 infection, including clinical outcome and host immune responses that may be important in preventing disease related to HHV-8, has not been elucidated. The present study characterized the clinical, immunologic, and virologic parameters of primary HHV-8 infection in 5 cases detected during a 15-year longitudinal study of 108 human immunodeficiency virus type 1 seronegative men in the Multicenter AIDS Cohort Study. Primary HHV-8 infection was associated with mild, nonspecific signs and symptoms of diarrhea, fatigue, localized rash, and lymphadenopathy. There were no alterations in numbers of CD4+ or CD8+ T cells or CD8+ T-cell interferon γ (IFN-γ) production to mitogen or nominal antigen. CD8+ cytotoxic T-lymphocyte precursor (CTLp) and IFN-γ reactivity were detected during primary HHV-8 infection, with broad specificity to 5 lytic cycle proteins of HHV-8 encoded by open reading frame 8 (ORF 8; glycoprotein B homolog of Epstein-Barr virus), ORF 22 (gH homolog), ORF 25 (major capsid protein homolog), ORF 26 (a minor capsid protein homolog), or ORF 57 (an early protein homolog), in association with increases in serum antibody titers and appearance of HHV-8 DNA in blood mononuclear cells. CD8+ T-cell responses to HHV-8 decreased by 2 to 3 years after primary infection. This antiviral T-cell response may control initial HHV-8 infection and prevent development of disease.

Identification of an HLA  A*0201–restricted CD8+T-cell epitope for the glycoprotein B homolog of human herpesvirus 8

Blood ◽  
2002 ◽  
Vol 99 (9) ◽  
pp. 3360-3366 ◽  
Author(s):  
Qiong J. Wang ◽  
Xiao-Li Huang ◽  
Giovanna Rappocciolo ◽  
Frank J. Jenkins ◽  
William H. Hildebrand ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Human Herpesvirus ◽  
Cd8 T Cell ◽  
Lytic Cycle ◽  
Human Herpesvirus 8 ◽  
Herpesvirus 8 ◽  
Ifn Γ

Abstract Human herpesvirus 8 (HHV-8; Kaposi sarcoma–associated herpesvirus)–specific cytotoxic T-lymphocyte (CTL) and interferon-γ (IFN-γ) responses to proteins produced during the lytic cycle of HHV-8 replication are mediated by HLA class I–restricted, CD8+ T cells. We have characterized the fine specificity of the CD8+ T-cell response to 25 peptides derived from 5 HHV-8 lytic cycle proteins based on a prediction model for HLA A*0201 binding motifs. One of the 25 HLA A*0201 peptides derived from the glycoprotein B (gB) homolog of Epstein-Barr virus (gB492-500; LMWYELSKI; single-letter amino acid codes) bound to HLA A*0201 and stimulated IFN-γ responses in CD8+ T cells from HHV-8+, HLA A*0201 persons, but not HHV-8–seronegative or non–HLA A*0201 persons. The peptide also induced IFN-γ and CTL reactivity to naturally processed gB protein. The peptide was a major immunogenic epitope of HHV-8 as indicated by induction of IFN-γ responses in peripheral blood mononuclear cells from 5 of 5 HHV-8 seropositive, HLA A*0201 persons when gB492-500 was presented by autologous dendritic cells. T-cell reactivity to gB492-500 was not related to detectable HHV-8 DNA in the blood. These data show that CD8+ T cells recognize an HLA A*0201–restricted epitope for HHV-8 lytic cycle protein gB, particularly when presented by dendritic cells. This epitope may be important in control of HHV-8 infection by CD8+ T cells.

scholarly journals Regulatory T Cell Effect on CD8+T Cell Responses to Human Herpesvirus 8 Infection and Development of Kaposi's Sarcoma

2017 ◽  
Vol 33 (7) ◽  
pp. 668-674 ◽  
Author(s):  
Lauren M. Lepone ◽  
Giovanna Rappocciolo ◽  
Paolo A. Piazza ◽  
Diana M. Campbell ◽  
Frank J. Jenkins ◽  
...  
Keyword(s):  
T Cell ◽  
Regulatory T Cell ◽  
Kaposi's Sarcoma ◽  
Human Herpesvirus ◽  
T Cell Responses ◽  
Kaposi’S Sarcoma ◽  
Cd8 T Cell ◽  
Human Herpesvirus 8 ◽  
Herpesvirus 8 ◽  
Cell Responses

The Response to Repeated Vaccination with PR1 and WT1 Peptides Admixed in Montanide Adjuvant Is Transient and Fails to Induce Sustained Anti-Leukemia Responses in Patients with Myeloid Malignancies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4096-4096
Author(s):  
Katayoun Rezvani ◽  
Agnes S. M. Yong ◽  
Stephan Mielke ◽  
Behnam Jafarpour ◽  
Bipin N. Savani ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Gm Csf ◽  
Cell Responses ◽  
Ifn Γ

Abstract Abstract 4096 Poster Board III-1031 We previously demonstrated the immunogenicity of a combined vaccine approach employing two leukemia-associated antigenic peptides, PR1 and WT1 (Rezvani Blood 2008). Eight patients with myeloid malignancies received one subcutaneous 0.3 mg and 0.5 mg dose each of PR1 and WT1 vaccines in Montanide adjuvant, with 100 μg of granulocyte-macrophage colony-stimulating factor (GM-CSF). CD8+ T-cell responses against PR1 or WT1 were detected in all patients as early as 1 week post-vaccination. However, responses were only sustained for 3-4 weeks. The emergence of PR1 or WT1-specific CD8+ T-cells was associated with a significant but transient reduction in minimal residual disease (MRD) as assessed by WT1 expression, suggesting a vaccine-induced anti-leukemia response. Conversely, loss of response was associated with reappearance of WT1 transcripts. We hypothesized that maintenance of sustained or at least repetitive responses may require frequent boost injections. We therefore initiated a phase 2 study of repeated vaccination with PR1 and WT1 peptides in patients with myeloid malignancies. Five patients with acute myeloid leukemia (AML) and 2 patients with myelodysplastic syndrome (MDS) were recruited to receive 6 injections at 2 week intervals of PR1 and WT1 in Montanide adjuvant, with GM-CSF as previously described. Six of 7 patients completed 6 courses of vaccination and follow-up as per protocol, to monitor toxicity and immunological responses. Responses to PR1 or WT1 vaccine were detected in all patients after only 1 dose of vaccine. However, additional boosting did not further increase the frequency of PR1 or WT1-specific CD8+ T-cell response. In 4/6 patients the vaccine-induced T-cell response was lost after the fourth dose and in all patients after the sixth dose of vaccine. To determine the functional avidity of the vaccine-induced CD8+ T-cell response, the response of CD8+ T-cells to stimulation with 2 concentrations of PR1 and WT1 peptides (0.1 and 10 μM) was measured by IC-IFN-γ staining. Vaccination led to preferential expansion of low avidity PR1 and WT1 specific CD8+ T-cell responses. Three patients (patients 4, 6 and 7) returned 3 months following the 6th dose of PR1 and WT1 peptide injections to receive a booster vaccine. Prior to vaccination we could not detect the presence of PR1 and WT1 specific CD8+ T-cells by direct ex-vivo tetramer and IC-IFN-γ assay or with 1-week cultured IFN-γ ELISPOT assay, suggesting that vaccination with PR1 and WT1 peptides in Montanide adjuvant does not induce memory CD8+ T-cell responses. This observation is in keeping with recent work in a murine model where the injection of minimal MHC class I binding peptides derived from self-antigens mixed with IFA adjuvant resulted in a transient effector CD8+ T cell response with subsequent deletion of these T cells and failure to induce CD8+ T cell memory (Bijker J Immunol 2007). This observation can be partly explained by the slow release of vaccine peptides from the IFA depot without systemic danger signals, leading to presentation of antigen in non-inflammatory lymph nodes by non-professional antigen presenting cells (APCs). An alternative explanation for the transient vaccine-induced immune response may be the lack of CD4+ T cell help. In summary these data support the immunogenicity of PR1 and WT1 peptide vaccines. However new approaches will be needed to induce long-term memory responses against leukemia antigens. To avoid tolerance induction we plan to eliminate Montanide adjuvant and use GM-CSF alone. Supported by observations that the in vivo survival of CD8+ T-effector cells against viral antigens are improved by CD4+ helper cells, we are currently attempting to induce long-lasting CD8+ T-cell responses to antigen by inducing CD8+ and CD4+ T-cell responses against class I and II epitopes of WT1 and PR1. Disclosures: No relevant conflicts of interest to declare.

scholarly journals IFN-γ-Inducible Protein-10 Is Essential for the Generation of a Protective Tumor-Specific CD8 T Cell Response Induced by Single-Chain IL-12 Gene Therapy

2001 ◽  
Vol 166 (11) ◽  
pp. 6944-6951 ◽  
Author(s):  
Ursula Pertl ◽  
Andrew D. Luster ◽  
Nissi M. Varki ◽  
Dirk Homann ◽  
Gerhard Gaedicke ◽  
...  
Keyword(s):  
Gene Therapy ◽  
T Cell ◽  
Cell Response ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Single Chain ◽  
Ifn Γ ◽  
Inducible Protein

CD8+ T lymphocyte response against extrahepatic biliary epithelium is activated by epitopes within NSP4 in experimental biliary atresia

2014 ◽  
Vol 307 (2) ◽  
pp. G233-G240 ◽  
Author(s):  
Shuaiyu Zheng ◽  
Hongyi Zhang ◽  
Xiaojin Zhang ◽  
Fei Peng ◽  
Xuyong Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Biliary Atresia ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Biliary Epithelium ◽  
Neonatal Mice ◽  
Ifn Γ

Interferon (IFN)-γ-driven and CD8+ T cell-dependent inflammatory injury to extrahepatic biliary epithelium (EHBE) is likely to be involved in the development of biliary atresia (BA). We previously showed that viral protein NSP4 is the pathogenic immunogen that causes biliary injury in BA. In this study, NSP4 or four synthetic NSP4 (NSP4157–170, NSP4144–152, NSP493–110, NSP424–32) identified by computer analysis as candidate CD8+ T cell epitopes were injected into neonatal mice. The pathogenic NSP4 epitopes were confirmed by studying extrahepatic bile duct injury, IFN-γ release and CD8+ T cell response against EHBE. The results revealed, at 7 days postinjection, inoculation of glutathione S-transferase (GST)-NSP4 caused EHBE injury and BA in neonatal mice. At 7 or 14 days postinject, inoculation of GST-NSP4, NSP4144–152, or NSP4157–170 increased IFN-γ release by CD8+ T cells, elevated the population of hepatic memory CD8+ T cells, and augmented cytotoxicity of CD8+ T cells to rhesus rotavirus (RRV)-infected or naive EHBE cells. Furthermore, depletion of CD8+ T cells in mice abrogated the elevation of GST-NSP4-induced serum IFN-γ. Lastly, parenteral immunization of mouse dams with GST-NSP4, NSP4144–152, or NSP4157–170 decreased the incidence of RRV-induced BA in their offspring. Overall, this study reports the CD8+ T cell response against EHBE is activated by epitopes within rotavirus NSP4 in experimental BA. Neonatal passive immunization by maternal vaccination against NSP4144–152 or NSP4157–170 is effective in protecting neonates from developing RRV-related BA.

scholarly journals CD4 regulatory T cells Control CD8 T cell responses to human Herpesvirus 8 lytic and latency proteins

2012 ◽  
Vol 7 (S1) ◽  
Author(s):  
Lauren Lepone ◽  
Giovanna Rappocciolo ◽  
Paolo Piazza ◽  
Mariel Jais ◽  
Frank J Jenkins ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Human Herpesvirus ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Human Herpesvirus 8 ◽  
Herpesvirus 8 ◽  
Cell Responses

scholarly journals Gamma Interferon Regulates Contraction of the Influenza Virus-Specific CD8 T Cell Response and Limits the Size of the Memory Population

2013 ◽  
Vol 87 (23) ◽  
pp. 12510-12522 ◽  
Author(s):  
Nayana Prabhu ◽  
Adrian W. Ho ◽  
Kenneth H. S. Wong ◽  
Paul Edward Hutchinson ◽  
Yen Leong Chua ◽  
...  
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Cell Population ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Memory Cell ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Ifn Γ

The factors that regulate the contraction of the CD8 T cell response and the magnitude of the memory cell population against localized mucosal infections such as influenza are important for generation of efficient vaccines but are currently undefined. In this study, we used a mouse model of influenza to demonstrate that the absence of gamma interferon (IFN-γ) or IFN-γ receptor 1 (IFN-γR1) leads to aberrant contraction of antigen-specific CD8 T cell responses. The increased accumulation of the effector CD8 T cell population was independent of viral load. Reduced contraction was associated with an increased fraction of CD8 T cells expressing the interleukin-7 receptor (IL-7R) at the peak of the response, resulting in enhanced numbers of memory/memory precursor cells in IFN-γ−/−and IFN-γR−/−compared to wild-type (WT) mice. Blockade of IL-7 within the lungs of IFN-γ−/−mice restored the contraction of influenza virus-specific CD8 T cells, indicating that IL-7R is important for survival and is not simply a consequence of the lack of IFN-γ signaling. Finally, enhanced CD8 T cell recall responses and accelerated viral clearance were observed in the IFN-γ−/−and IFN-γR−/−mice after rechallenge with a heterologous strain of influenza virus, confirming that higher frequencies of memory precursors are formed in the absence of IFN-γ signaling. In summary, we have identified IFN-γ as an important regulator of localized viral immunity that promotes the contraction of antigen-specific CD8 T cells and inhibits memory precursor formation, thereby limiting the size of the memory cell population after an influenza virus infection.

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