Identification of a Novel Immunodominant HLA-B*07

Abstract

Adenovirus infections of immunocompromised patients, particularly following allogeneic hematopoietic stem cell transplantation, are associated with morbidity and mortality. Immunotherapy by adoptive transfer of hexon-specific and penton-specific T cells has been successfully applied, but many approaches are impeded by the low number of HLA class I-restricted adenoviral peptide epitopes described to date. We use a novel method to identify naturally presented adenoviral peptide epitopes from infected human cells, ectopically expressing defined HLA, using peptide elution and liquid chromatography-mass spectrometry analysis. We show that the previously described HLA-A*01:01-restricted peptide epitope LTDLGQNLLY from hexon protein is naturally presented, and demonstrate the functionality of LTDLGQNLLY-specific T cells. We further identify a novel immunodominant HLA-B*07:02-restricted peptide epitope VPATGRTLVL from protein 13.6 K, and demonstrate the high proliferative, cytotoxic, and IFN-γ-producing capacity of peptide-specific T cells. Lastly, LTDLGQNLLY-specific T cells can be detected ex vivo following adoptive transfer therapy, and LTDLGQNLLY-specific and VPATGRTLVL-specific T cells have memory phenotypes ex vivo. Given their proliferative and cytotoxic capacity, such epitope-specific T cells are promising candidates for adoptive T-cell transfer therapy of adenovirus infection.

Discovery of immunodominant T-cell epitopes reveals penton protein as a second immunodominant target in human adenovirus infection

“…Immunodominance of these six candidates was verified by T-cell immunoassays and T-cell immunomonitoring in HAdV-infected HSCT patients, which delineated the significance of the identified CD8 + T-cell epitopes in vivo. Guenther et al identified the naturally presented HAdV epitopes LTDLGQNLLY and VPATGRTLVL [ 19 ], for which we obtained high prediction scores. These results underline the high prediction accuracy of HLA-class I epitopes obtained by the allele-specific prediction algorithms utilized in the present study.…”

“…In addition, a lower peptide concentration for in vitro T-cell activation was required compared to the nonamer, indicating that the 15-mer peptide is an optimal CD4 + T-cell epitope [ 22 , 23 ]. Guether et al identified the decamer of the known immunodominant HLA-A01-restricted hexon-derived peptide (A01Hexon TDLG , L TDLGQNLLY) as a naturally presented T-cell epitope that induces peptide-specific T cells with a higher proliferative, cytotoxic, and IFN-γ-producing capacity than T cells specific for the shorter peptide TDLGQNLLY [ 19 ]. Therefore, we will evaluate the immunogenic potential of longer peptides from the novel identified low immunodominant B08Hexon DLQD peptide in a future study.…”

“…Occasionally, types of species HAdV-B can be observed in adult HSCT recipients [ 18 ]. The major capsid protein hexon serves as an immunodominant target antigen across the different HAdV types, but few hexon-derived epitopes have been identified as immunodominant so far [ 13 , 19 – 23 ]. Most of these epitopes are highly conserved, demonstrating that HAdV-specific T cells can cross-react across HAdV species and may therefore provide protection against a wide range of HAdV types [ 20 ].…”

Identification of HCMV-derived T cell epitopes in seropositive individuals through viral deletion models

“…To date, the identification of most HCMV-specific T cell targets has been based on prediction methods ( Elkington et al, 2003 ; Hebart et al, 2002 ; Nastke et al, 2005 ) or the use of overlapping peptides ( Sylwester et al, 2005 ). The approach of direct isolation of viral ligands from infected target cells, successfully used for some viral infections ( Croft et al, 2019 ; Günther et al, 2015 ; McMurtrey et al, 2008 ; Meyer et al, 2008 ; Ternette et al, 2016 ), has been cumbersome due to strict control of peptide presentation by HCMV-encoded HLA class I (HLA-I) immunoevasins ( Ahn et al, 1997 ; Furman et al, 2002 ; Gewurz et al, 2001 ; Hegde et al, 2002 ; Jones et al, 1996 ; Odeberg et al, 2003 ). Glycoproteins encoded by the US6 gene family are able to impair the stability and localization of HLA-I.…”

Monitoring of adenovirus (ADV)‐specific T cells in a boy with ADV pneumonia and disseminated disease after lung transplantation

“…For clearance of ADV infection, the formation of a protective ADV‐specific T‐cell response is mandatory, which has been thoroughly shown in stem cell transplant (SCT) recipients . The major capsid protein hexon serves as immunodominant target antigen across the different ADV serotypes . Unfortunately, only a few immunogenic hexon‐derived epitopes, restricted to only 3 human leukocyte antigen (HLA) alleles, have been identified so far.…”