Adenovirus hexon T-cell epitope is recognized by most adults and is restricted by HLA DP4, the most common class II allele

Tang, Jie; Olive, Melanie; Champagne, Kelly; Flomenberg, Neal; Eisenlohr, Laurence C.; Hsu, Susan H.; Flomenberg, Phyllis

doi:10.1038/sj.gt.3302316

Cited by 58 publications

(59 citation statements)

References 22 publications

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“…[14][15][16][17][18][19] Since these epitopes are largely conserved, specific T cells were shown to be cross-reactive towards HAdV serotypes from different HAdV subgroups and may, therefore, provide protection against a wide range of HAdV serotypes. HAdV hexon-specific T cells have been reported to be detectable in 72% of healthy donors, but may be present at very low frequencies in the remaining donors.…”

Section: Introductionmentioning

confidence: 99%

Combined CD8+ and CD4+ adenovirus hexon-specific T cells associated with viral clearance after stem cell transplantation as treatment for adenovirus infection

Zandvliet¹,

Falkenburg²,

Liempt³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundHuman adenovirus can cause morbidity and mortality in immunocompromised patients after allogeneic stem cell transplantation. Reconstitution of adenovirus-specific CD4 + T cells has been reported to be associated with sustained protection from adenovirus disease, but epitope specificity of these responses has not been characterized. Since mainly CD4 + T cells and no CD8 + T cells specific for adenovirus have been detected after allogeneic stem cell transplantation, the relative contribution of adenovirus-specific CD4 + and CD8 + T cells in protection from adenovirus disease remains to be elucidated. Design and MethodsThe presence of human adenovirus hexon-specific T cells was investigated in peripheral blood of pediatric and adult allogeneic stem cell transplant recipients, who showed spontaneous resolution of disseminated adenovirus infection. Subsequently, a clinical grade method was developed for rapid generation of adenovirus-specific T-cell lines for adoptive immunotherapy. ResultsClearance of human adenovirus viremia coincided with emergence of a coordinated CD8 + and CD4 + T-cell response against adenovirus hexon epitopes in patients after allogeneic stem cell transplantation. Activation of adenovirus hexon-specific CD8 + and CD4 + T cells with a hexon protein-spanning peptide pool followed by interferon-γ-based isolation allowed rapid expansion of highly specific T-cell lines from healthy adults, including donors with very low frequencies of adenovirus hexon-specific T cells. Adenovirus-specific T-cell lines recognized multiple MHC class I and II restricted epitopes, including known and novel epitopes, and efficiently lysed human adenovirus-infected target cells. ConclusionsThis study provides a rationale and strategy for the adoptive transfer of donor-derived human adenovirus hexon-specific CD8 + and CD4 + T cells for the treatment of disseminated adenovirus infection after allogeneic stem cell transplantation.Key words: allogeneic stem cell transplantation, adoptive immunotherapy, adenovirus infection, adenovirus-specific T cells.Citation: Zandvliet ML, Falkenburg JH, van Liempt E, Lankester AC, Kalpoe JS, Kester MG, van der Steen DM, van Tol MJ, Willemze R, Guchelaar HJ, Schilham MW, and Meij P. Combined CD8 + and CD4 + adenovirus hexon-specific T cells associated with viral clearance after stem cell transplantation as treatment for adenovirus infection. Haematologica 2010;95(11):1943-1951. doi:10.3324/haematol.2010

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Section: Introductionmentioning

confidence: 99%

Combined CD8+ and CD4+ adenovirus hexon-specific T cells associated with viral clearance after stem cell transplantation as treatment for adenovirus infection

Zandvliet¹,

Falkenburg²,

Liempt³

et al. 2010

Haematologica

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“…1B, and results are summarized in Table I. Two clones recognized II64, which contains a conserved epitope II 910 -924 that has recently been described (29,40). Proliferation was also observed against this minimal epitope, indicating that these two HAdV-specific clones specifically recognized this II 910 -924 epitope contained within peptide II64.…”

Section: Characterization Of Hadv-specific Cd4 ϩ T Cell Clonesmentioning

confidence: 85%

Adenovirus-Specific CD4+ T Cell Clones Recognizing Endogenous Antigen Inhibit Viral Replication In Vitro through Cognate Interaction

Heemskerk

Vreeswijk

Veltrop-Duits

et al. 2006

The Journal of Immunology

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Human adenovirus (HAdV) infection is a frequent and potentially severe complication following allogeneic stem cell transplantation in children. Because treatment with antiviral drugs is often ineffective, adoptive transfer of donor-derived HAdV-specific T cells able to control viral replication of HAdV of multiple serotypes may be an option for therapy. In healthy donors, predominantly HAdV-specific T cells expressing CD4 are detected. In this study, a preclinical in vitro model was used to measure the antiviral effect of HAdV-specific CD4+ T cells. CD4+ HAdV-specific T cell clones restricted by HLA class II molecules were generated and most of these clones recognized conserved peptides derived from the hexon protein. These cross-reactive T cell clones were able to control viral replication of multiple serotypes of HAdV in EBV-transformed B cells (B-LCL), melanoma cells (MJS) and primary bronchial epithelial cells through cognate interaction. The HAdV-specific CD4+ T cell clones were able to specifically lyse infected target cells using a perforin-dependent mechanism. Antigenic peptides were also presented to the CD4+ T cell clones when derived from endogenously produced hexon protein. Together, these results show that cross-reactive HAdV-specific CD4+ T cells can control replication of HAdV in vitro and provide a rationale for the use of HAdV-specific T cells in adoptive immunotherapy protocols for control of life-threatening HAdV-infections in immunocompromised patients.

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“…Subsequently, several groups have further characterized Ad-specific human CTLs and each has confirmed that responses are restricted primarily to conserved regions of hexon (Leen et al, 2004a(Leen et al, , b, 2008Olive et al, 2001Olive et al, , 2002Tang et al, 2004Tang et al, , 2006Veltrop-Duits et al, 2006). Recent data have also revealed that two early-region proteins, DNA polymerase and DNA-binding protein, may also be recognized by Ad-specific CTLs (Joshi et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…We confirmed that SP98/SP99, each containing the TLLYVLFEV sequence, were recognized in the context of both DPB1*0401 and DPB1*0402 and further identified epitopes restricted by DQB*0402 and Cw*0702 within H906-928. Indeed, multiple investigators have reported hexon-specific responses within this region after natural infection (Tang et al, 2004(Tang et al, , 2006, after priming with intact Ad (Olive et al, 2002) or a modified Ad vector , and using 30-mer hexon peptides . Predominantly CD4 + T cells respond to Ad in healthy adults and paediatric patients post-HPCT, which contrasts with the largely CD8 + T-cell response to most viral pathogens (Appay et al, 2008;Yewdell & Bennink, 1992).…”

Section: Discussionmentioning

confidence: 99%

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Generation of cytotoxic T-cell lines using overlapping pentadecapeptides derived from conserved regions of the adenovirus hexon protein

Zhu¹,

Xu²,

Tsao³

et al. 2010

Journal of General Virology

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Many of the 51 serotypes of adenovirus have been associated with clinically relevant infection. Adenovirus can disseminate rapidly in patients with a compromised immune system, such as that which occurs secondary to haematopoietic progenitor-cell transplantation. The higher rate of infection in recipients of T cell-depleted grafts and in those undergoing T cell-targeted treatment during graft versus host disease demonstrates the importance of a T-cell response in preventing disseminated infection. Studies have shown that the memory response to adenovirus is directed primarily to the hexon protein and is dominated by CD4 + T cells, probably due to the ability of the virus to block its presentation on HLA class I antigens. We have developed an approach to expand adenovirus-specific T cells using a pool of overlapping pentadecapeptides derived from selected conserved regions of hexon. We characterized responses to identify the peptides that are recognized, the responding T-cell subsets and their HLA restriction. Of eight lines that were characterized extensively, seven included both CD4 + and CD8 + T cells and each recognized between two and eight unique peptide sequences. By focusing the response on the conserved sequences of hexon, the cell lines are likely to recognize most of the serotypes responsible for clinically relevant disease. The 15 aa peptides used to prime the responses are more likely than whole virus or longer peptides to expand the less frequent CD8 + memory subset. Lines prepared by using our method may be more effective in adoptive immunotherapy protocols designed to prevent or treat disseminated adenovirus infections in high-risk patients.

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Adenovirus hexon T-cell epitope is recognized by most adults and is restricted by HLA DP4, the most common class II allele

Cited by 58 publications

References 22 publications

Combined CD8+ and CD4+ adenovirus hexon-specific T cells associated with viral clearance after stem cell transplantation as treatment for adenovirus infection

Combined CD8+ and CD4+ adenovirus hexon-specific T cells associated with viral clearance after stem cell transplantation as treatment for adenovirus infection

Adenovirus-Specific CD4+ T Cell Clones Recognizing Endogenous Antigen Inhibit Viral Replication In Vitro through Cognate Interaction

Generation of cytotoxic T-cell lines using overlapping pentadecapeptides derived from conserved regions of the adenovirus hexon protein

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