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

Abstract

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.

Distinguishing Signal From Noise in Immunopeptidome Studies of Limiting-Abundance Biological Samples: Peptides Presented by I-Ab in C57BL/6 Mouse Thymus

“…Also, the distribution of peptides eluted from the beads-only column of the membrane preparation looked similar to the beads-only eluted peptides of the whole cell preparation (Supplementary Figure S3B). These results indicated that a membrane fractionation strategy as used previously (13,36,37) was not helpful in removing the non-specific peptides. Second, we tested whether restricting the analysis to peptides identified reproducibly in every sample would help to remove non-specific peptides, with the idea that the non-specific peptides might be present sporadically as a result of low-frequency random binding or sampling events.…”

Heterogeneity of Genetic Admixture Determines SLE Susceptibility in Mexican

“…The ancestry variation in individuals with SLE, as said before, could mean that some non-autochthonous HLA alleles have been conserved because these alleles represent an immunogenetic advantage, as demonstrated for HLA-DRB1 ∗ 03. For instance, some naturally processed HLA-DR3-restricted Human herpesvirus 6B (HHV-6B) peptides are recognized broadly with polyfunctional and cytotoxic CD4 T-cell responses ( Becerra-Artiles et al, 2019 ). However, this convenient immunogenetic mechanism for clearing infections might be the detonator for immunological hyperreactivity, which marks the onset of the disease.…”

Mass Spectrometry in Virological Sciences

“…They were able to activate T cells recruiting from CD3+ and CD4+ subpopulations. In natural conditions, observed T-cells reactivity toward presented antigens, identified during the investigation, allows controlling HHV-6B infection at a reasonable level (Becerra-Artiles et al, 2019). Ternette et al (2016) immunoprecipitated peptides bound to HLA class I complexes from HIV-1-infected primary CD4+ T cells and C8166 cell lines, and further identified those by LC-MS/MS.…”