MHC-E–Restricted CD8+ T Cells Target Hepatitis B Virus–Infected Human Hepatocytes

Burwitz, Benjamin J.; Hashiguchi, Patrick K; Mansouri, Mahboubeh; Meyer, Christine; Gilbride, Roxanne M.; Biswas, Sreya; Womack, Jennie; Reed, Jason S.; Wu, Helen L.; Axthelm, Michael K.; Hansen, Scott G.; Picker, Louis J.; Früh, Klaus; Sacha, Jonah B.

doi:10.4049/jimmunol.1900795

Cited by 19 publications

(26 citation statements)

References 38 publications

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“…A series of studies in rhesus macaques (RM) vaccinated with modified rhesus CMV (RhCMV) vectors carrying pathogen-encoded Ags showed that the vaccineinduced protection was largely, if not fully, dependent on Mamu-E (ortholog of HLA-E in RM)-restricted T cell responses in the context of Plasmodium knowlesi and SIV infections (15,16). More recently, Mamu-E-restricted hepatitis B virusspecific CD8 + T cells induced by a modified RhCMV vector were able to recognize hepatitis B virus-infected primary hepatocytes derived from both RM and humans, further supporting the potential of these unconventional T cells as vaccine targets in humans (17).…”

mentioning

confidence: 94%

Peptide Binding to HLA-E Molecules in Humans, Nonhuman Primates, and Mice Reveals Unique Binding Peptides but Remarkably Conserved Anchor Residues

Ruibal

Franken

Meijgaarden

et al. 2020

The Journal of Immunology

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Ag presentation via the nonclassical MHC class Ib molecule HLA-E, with nearly complete identity between the two alleles expressed in humans, HLA-E*01:01 and HLA-E*01:03, can lead to the activation of unconventional T cells in humans. Despite this virtual genetic monomorphism, differences in peptide repertoires binding to the two allelic variants have been reported. To further dissect and compare peptide binding to HLA-E*01:01 and HLA-E*01:03, we used an UV-mediated peptide exchange binding assay and an HPLC-based competition binding assay. In addition, we investigated binding of these same peptides to Mamu-E, the nonhuman primate homologue of human HLA-E, and to the HLA-E–like molecule Qa-1b in mice. We next exploited the differences and homologies in the peptide binding pockets of these four molecules to identify allele specific as well as common features of peptide binding motifs across species. Our results reveal differences in peptide binding preferences and intensities for each human HLA-E variant compared with Mamu-E and Qa-1b. Using extended peptide libraries, we identified and refined the peptide binding motifs for each of the four molecules and found that they share main anchor positions, evidenced by conserved amino acid preferences across the four HLA-E molecules studied. In addition, we also identified differences in peptide binding motifs, which could explain the observed variations in peptide binding preferences and affinities for each of the four HLA-E–like molecules. Our results could help with guiding the selection of candidate pathogen-derived peptides with the capacity to target HLA-E–restricted T cells that could be mobilized in vaccination and immunotherapeutic strategies.

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mentioning

confidence: 94%

Peptide Binding to HLA-E Molecules in Humans, Nonhuman Primates, and Mice Reveals Unique Binding Peptides but Remarkably Conserved Anchor Residues

Ruibal

Franken

Meijgaarden

et al. 2020

The Journal of Immunology

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“…In a TAP deficient environment (viral infection/tumor), loading of the canonical leader peptide sequence is hindered (11) leading to a large (>500) HLA-E bound peptide repertoire. Identification of HLA-E restricted CD8 effector T-cell responses against cytomegalovirus (CMV) (12)(13)(14)(15)(16)(17), hepatitis C virus (HCV) (18), Epstein-Barr virus (EBV) (19), and recently hepatitis B virus (HBV) (20) points to the existence of a subset of human CD8 T cells that can sense pathogen with their TCRs in the context of HLA-E. Recognition of TCR by peptide (CMV-UL40) presented via HLA-E was first recognized in studies using NK-CTL clones (21,22).…”

Section: Introductionmentioning

confidence: 99%

“…Since the Mamu-E gene is highly conserved in both New and Old World primates, it is possible that HLA-E retains the structural and functional potential to be targeted by substantial adaptive T-cell responses after HIV-1 infection (34). Furthermore, recent data on surface upregulation of HLA-E in viral infections (20,30,35) suggests that HLA-E restricted HIV specific CD8 T-cell responses may play an important role in CD8 T-cell surveillance. Despite these potential benefits, targeting of HLA-E restricted HIV specific CD8 T cells in HIV infection and characterizing their functionality has not been addressed before.…”

Section: Introductionmentioning

confidence: 99%

HLA-E–restricted HIV-1–specific CD8+ T cell responses in natural infection

Bansal

Gehre

Ali

et al. 2021

Journal of Clinical Investigation

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MHC-E, a non-classical MHC molecule, restricted CD8 T-cell responses have been associated with protection in an SIV/rhesus macaque model. The biological relevance of HLA-E restricted CD8 T-cell responses in HIV infection however remains unknown. In this study, CD8 T cells responding to HIV-1 Gag peptides presented by HLA-E were analyzed. Using in-vitro assays, we observed HLA-E restricted T-cell responses to what we believe to be a newly identified subdominant Gag-KL9 as well as a well-described immuno-dominant Gag-KF11 epitope in T-cell lines derived from chronically HIV-infected patients and also primed from healthy donors. Blocking of the HLA-E/KF11 binding by the B7 signal peptide resulted in decreased CD8 T-cell responses. KF11 presented via HLA-E in HIV infected cells was recognized by antigen specific CD8 T cells. Importantly, bulk CD8 T cells obtained from HIV infected individuals recognized infected cells via HLA-E presentation. Ex-vivo analyses at the epitope level showed a higher responder frequency of HLA-E restricted responses to KF11 compared to KL9.Taken together, our findings of HLA-E restricted HIV specific immune responses offer intriguing and possibly paradigm shifting insights into factors that contribute to the immuno-dominance of CD8 T-cell responses in HIV infection.

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“…Similarly, vaccination of RM with RhCMV/hepatitis B virus (HBV) elicited Mamu-E-restricted T-cells producing IFN-γ upon recognition of both RM-and human-derived HBV-infected primary hepatocytes in vitro. 24,25 Plasmodium knowlesi (Pk) challenge of RhCMV/Pk-vaccinated RM led to delayed parasitemia, again partially dependent on Mamu-E-restricted T-cells. 26 A significant reduction in the magnitude of Mtb infection and disease after RhCMV/ TB vaccination in RM was observed compared with unvaccinated animals.…”

Section: Studies On Hla-e-restricted T-cells In Experimental Vaccination Studiesmentioning

confidence: 99%

“…Mamu‐E–restricted T‐cells from these animals were able to recognize SIV‐infected CD4 + T‐cells as shown by IFN‐γ and TNF‐α production, a response which could be blocked by the HLA‐E–specific binding VL9 peptide. Similarly, vaccination of RM with RhCMV/hepatitis B virus (HBV) elicited Mamu‐E–restricted T‐cells producing IFN‐γ upon recognition of both RM‐ and human‐derived HBV‐infected primary hepatocytes in vitro 24,25 . Plasmodium knowlesi (Pk) challenge of RhCMV/Pk‐vaccinated RM led to delayed parasitemia, again partially dependent on Mamu‐E–restricted T‐cells 26 .…”

Section: Hla‐e–restricted T‐cellsmentioning

confidence: 99%

The role of donor‐unrestricted T‐cells, innate lymphoid cells, and NK cells in anti‐mycobacterial immunity

Ruibal

Voogd

Joosten

et al. 2021

Immunological Reviews

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MHC-E–Restricted CD8+ T Cells Target Hepatitis B Virus–Infected Human Hepatocytes

Cited by 19 publications

References 38 publications

Peptide Binding to HLA-E Molecules in Humans, Nonhuman Primates, and Mice Reveals Unique Binding Peptides but Remarkably Conserved Anchor Residues

Peptide Binding to HLA-E Molecules in Humans, Nonhuman Primates, and Mice Reveals Unique Binding Peptides but Remarkably Conserved Anchor Residues

HLA-E–restricted HIV-1–specific CD8+ T cell responses in natural infection

The role of donor‐unrestricted T‐cells, innate lymphoid cells, and NK cells in anti‐mycobacterial immunity

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