Identification of novel CD8+ T cell epitopes in human herpesvirus 6B U11 and U90

Halawi, Mustafa; Khan, Naeem; Blake, Neil

doi:10.1002/iid3.55

Cited by 10 publications

(15 citation statements)

References 47 publications

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“…As previously observed [56], we found that infection of SupT1.CIITA cells with HHV-6B resulted in downregulation of MHC-class I. It is possible that when the cytotoxic CD8 T cells have been compromised by any of the immunomodulatory mechanisms used by the virus to interfere with MHC-I presentation and CD8 response [10,13,18,19,21], CD4 T cells may become more prominent in the control of the virus. A more detailed phenotypic and functional characterization of CD4 T cell responding to HHV-6B in healthy donors could shed light on the specific responding subset, as well as its effector and functional capacities.…”

supporting

confidence: 79%

Naturally processed HLA‐DR3‐restricted HHV‐6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T‐cell responses

et al. 2019

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Human herpes virus 6B (HHV‐6B) is a widespread virus that infects most people early in infancy and establishes a chronic life‐long infection with periodic reactivation. CD4 T cells have been implicated in control of HHV‐6B, but antigenic targets and functional characteristics of the CD4 T‐cell response are poorly understood. We identified 25 naturally processed MHC‐II peptides, derived from six different HHV‐6B proteins, and showed that they were recognized by CD4 T‐cell responses in HLA‐matched donors. The peptides were identified by mass spectrometry after elution from HLA‐DR molecules isolated from HHV‐6B‐infected T cells. The peptides showed strong binding to matched HLA alleles and elicited recall T‐cell responses in vitro. T‐cell lines expanded in vitro were used for functional characterization of the response. Responding cells were mainly CD3+CD4+, produced IFN‐γ, TNF‐α, and low levels of IL‐2, alone or in combination, highlighting the presence of polyfunctional T cells in the overall response. Many of the responding cells mobilized CD107a, stored granzyme B, and mediated specific killing of peptide‐pulsed target cells. These results highlight a potential role for polyfunctional cytotoxic CD4 T cells in the long‐term control of HHV‐6B infection.

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confidence: 79%

Naturally processed HLA‐DR3‐restricted HHV‐6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T‐cell responses

et al. 2019

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“…The novel prevalent antigen U95, recognized by 44% of participants and confirmed by peptides, has no known HCMV homolog but is a highly expressed immediate early gene (46). Therefore, it may also be a rational target for cell-based immunotherapies alongside the immediate early U90 protein, a previously described antigen (31,32,34). Peptide epitopes confirmed here for U14, U90, and U95 had sequence homology to the related betaherpesviruses HHV-6A (all epitopes) and HHV-7 (nine epitopes) (see Table S2 in the supplemental material), suggesting possible cross-reactivity.…”

Section: Discussionmentioning

confidence: 99%

“…Because HHV-6 and CMV are genetically related betaherpesviruses, some studies have focused on the HHV-6 homologs of known CMV antigenic proteins. These studies have identified HHV-6 U11, U14, U54, and U90, the homologs of CMV UL32, UL25, UL82/83, and IE1, respectively, as targets for CD4 or CD8 T cells (31)(32)(33)(34). Other studies have taken a cross-sectional approach by testing libraries of peptides that were predicted to bind to a particular HLA allele: DRB1*0101 for CD4 T cells (30,35) or HLA-B*0801 for CD8 T cells (36).…”

mentioning

confidence: 99%

Genome-Wide Approach to the CD4 T-Cell Response to Human Herpesvirus 6B

Hanson

Цветкова

Rerolle

et al. 2019

J Virol

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Human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV) are populationprevalent betaherpesviruses with intermittent lytic replication that can be pathogenic in immunocompromised hosts. Elucidation of the adaptive immune response is valuable for understanding pathogenesis and designing novel treatments. Knowledge of T-cell antigens has reached the genome-wide level for CMV and other human herpesviruses, but study of HHV-6 is at an earlier stage. Using rare-cell enrichment combined with an HLA-agnostic, proteome-wide approach, we queried HHV-6B-specific CD4 T cells from 18 healthy donors with each known HHV-6B protein. We detected a low abundance of HHV-6-specific CD4 T cells in blood; however, the within-person CD4 T-cell response is quite broad: the median number of open reading frame (ORF) products recognized was nine per person. Overall, the data expand the number of documented HHV-6B CD4 T-cell antigens from approximately 11 to 60. Epitopes in the proteins encoded by U14, U90, and U95 were mapped with synthetic peptides, and HLA restriction was defined for some responses. Intriguingly, CD4 T-cell antigens newly described in this report are among the most population prevalent, including U73, U72, U95, and U30. Our results indicate that selection of HHV-6B ORFs for immunotherapy should consider this expanded panel of HHV-6B antigens. RESULTS Peripheral blood of healthy donors contains HHV-6B-specific CD4 T cells that can be enriched in vitro.The initial cohort of 53 healthy donors was 34% male, and the median age at the time of blood draw was 40 years (range, 21 to 68 years). To ascertain the frequency of HHV-6B-specific CD4 T cells in peripheral blood, peripheral blood mononuclear cells (PBMCs) were assayed by an interleukin-2 (IL-2)/interferon gamma (IFN-␥) intracellular cytokine cytometry (ICC) assay (Fig. 1A). Donors had virus-specific cell populations that were of low abundance but clearly discernible in most subjects. Responses were typically less than 0.1% of total CD4 T cells, with an overall median of 0.048% (Fig. 1B).Given the low abundance of HHV-6-reactive CD4 T cells in PBMCs, we enriched these cells from 42 donors prior to interrogation of the HHV-6B protein library. These donors were chosen based on PBMC availability and a detectable response to HHV-6B ex vivo.

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“…However, in contrast to those of other human herpesviruses, HHV-6-specific T cells have been difficult to characterize so far. Indeed, HHV-6-specific T-cell responses were reported to be absent or of really low frequency in peripheral blood (20,21,23,32,33), particularly in regard to CD8 ϩ T cells (34). It has also been reported that HHV-6A impacts T cell subsets differentially; i.e., in response to HHV-6A stimulation, naive or central memory cells were more prone to apoptosis, whereas proliferation was increased for the late memory compartment (35).…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, in contrast to that for HCMV, knowledge of HHV-6-specific T-cell responses is limited. This caveat may result from the difficulty of detecting HHV-6-specific T cells ex vivo in healthy adults (19)(20)(21). Indeed, most studies have performed analyses after in vitro expansion (22,23).…”

mentioning

confidence: 99%

Phenotypic and Functional Differences between Human Herpesvirus 6- and Human Cytomegalovirus-Specific T Cells

Fastenackels

Bayard

Larsen

et al. 2019

J Virol

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Human herpesvirus 6 (HHV-6) infects >90% of the population and establishes a latent infection with asymptomatic episodes of reactivation. However, HHV-6 reactivation is associated with morbidity and sometimes mortality in immunocompromised patients. To date, control of the virus in healthy virus carriers and the failure to control it in patients with disease remain poorly understood. In particular, knowledge of HHV-6-specific T-cell responses is limited. Here, we characterized HHV-6A- and HHV-6B-specific CD4+ and CD8+ T-cell responses from peripheral blood mononuclear cells (PBMCs) of healthy donors. We studied the phenotype of effector HHV-6-specific T cells ex vivo, as well as of induced specific suppressive regulatory CD4+ T cells in vitro poststimulation, in comparison to human cytomegalovirus (HCMV) responses. Compared to that for HCMV, we show that ex vivo T-cell reactivity in peripheral blood is detectable but at very low frequency, both for HHV-6A and -6B viruses. Interestingly, the phenotype of the specific T cells also differs between the viruses. HHV-6A- and HHV-6B-specific CD4+ T lymphocytes are less differentiated than HCMV-specific T cells. Furthermore, we show a higher frequency of HHV-6-specific suppressive regulatory T cells (eTregs) than HCMV-specific eTregs in coinfected individuals. Despite the strong similarity of HHV-6 and HCMV from a virologic point of view, we observed immunological differences, particularly in relation to the frequency and phenotype of effector/memory and regulatory virus-specific T cells. This suggests that different immune factors are solicited in the control of HHV-6 infection than in that of HCMV infection. IMPORTANCE T cells are central to an effective defense against persistent viral infections that can be related to human cytomegalovirus (HCMV) or human herpesvirus 6 (HHV-6). However, knowledge of HHV-6-specific T-cell responses is limited. In order to deepen our knowledge of T-cell responses to HHV-6, we characterized HHV-6A- and HHV-6B-specific CD4+ and CD8+ T-cell responses directly ex vivo from healthy coinfected blood donors. Despite the strong similarity of HHV-6 and HCMV from a virologic point of view, we observed immunological differences, particularly in relation to the frequency and phenotype of effector/memory and regulatory virus-specific T cells. This suggests that different immune factors are solicited in the control of HHV-6 infection than in that of HCMV infection. Our findings may encourage immunomonitoring of patients with viral replication episodes to follow the emergence of effector versus regulatory T cells.

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Identification of novel CD8+ T cell epitopes in human herpesvirus 6B U11 and U90

Cited by 10 publications

References 47 publications

Naturally processed HLA‐DR3‐restricted HHV‐6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T‐cell responses

Naturally processed HLA‐DR3‐restricted HHV‐6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T‐cell responses

Genome-Wide Approach to the CD4 T-Cell Response to Human Herpesvirus 6B

Phenotypic and Functional Differences between Human Herpesvirus 6- and Human Cytomegalovirus-Specific T Cells

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