Characterization of Magnitude and Antigen Specificity of HLA-DP, DQ, and DRB3/4/5 Restricted DENV-Specific CD4+ T Cell Responses

Grifoni, Alba; Moore, Eugene; Voic, Hannah; Sidney, John; Phillips, Elizabeth; Jadi, Ramesh; Mallal, S.; Silva, Aruna Dharshan De; Silva, Aravinda M. de; Peters, Bjoern; Weiskopf, Daniela; Sette, Alessandro

doi:10.3389/fimmu.2019.01568

Cited by 36 publications

(36 citation statements)

References 46 publications

(69 reference statements)

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“…HLA typing was performed by an ASHI-accredited laboratory at Murdoch University (Western Australia) for Class II (DRB1, DRB3/4/5, DQA1/DQB1, DPB1) as previously described (17,18,30). Part of the peptide synthesis was either pooled in small mesopools, containing 10 peptides each, or pooled together with all the gE peptides and sequentially lyophilized as previously described to generate a gE Megapool(2).…”

Section: Study Subjects Pbmcs Isolation and Hla Typingmentioning

confidence: 99%

Identification and characterization of CD4+ T cell epitopes after Shingrix vaccination

Voic¹,

Vries

Sidney³

et al. 2020

Preprint

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Infections with varicella zoster virus (VZV), a member of the Herpesviridae family, are associated with a range of clinical manifestations. Primary infection with VZV causes chicken pox, and due to the virus’s capacity to remain latent in neurons, it can reactivate later in life causing herpes zoster (HZ), also known as shingles. Two different licensed vaccines are available to prevent HZ, either based on a live attenuated VZV strain (Zostavax) or on adjuvanted gE recombinant protein (Shingrix). While Zostavax efficacy wanes with age, Shingrix protection retains its efficacy in elderly subjects (80 years of age and beyond). In this context, studies to evaluate the potential role of T cell immunity as a correlate of protection and Shingrix efficacy are of interest. In this study, we characterized Shingrix specific ex vivo CD4 T cell responses in the context of natural exposure and HZ vaccination using pools of predicted epitopes. We show that T cell reactivity following natural infection and Zostavax vaccination dominantly targets non-structural proteins, while Shingrix vaccination redirects dominant reactivity to target gE. We mapped the gE-specific responses following Shingrix vaccination to 89 different gE epitopes, 34 of which accounted for 80% of the response. Using antigen presentation assays and single HLA molecule transfected lines, we experimentally determined HLA restrictions for 94 different donor/peptide combinations. Finally, we used our results as a training set to assess strategies to predict restrictions based on measured or predicted HLA binding and the corresponding HLA types of responding subjects.ImportanceUnderstanding the T cell profile associated with the protection observed in elderly vaccines following Shingrix vaccination is relevant to the general definition of correlates of vaccine efficacy. Our study enables these future studies by clarifying patterns of immunodominance associated with Shingrix vaccination, as opposed to natural infection or Zostavax vaccination. Identification of epitopes recognized by Shingrix-induced CD4 T cells vaccinees, and their associated HLA restrictions, enables the generation of tetrameric staining reagents, and more broadly the capability to characterize specificity, magnitude and phenotype of VZV specific T cells.

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Section: Study Subjects Pbmcs Isolation and Hla Typingmentioning

confidence: 99%

Identification and characterization of CD4+ T cell epitopes after Shingrix vaccination

Voic¹,

Vries

Sidney³

et al. 2020

Preprint

Self Cite

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“…One study examining the HLA-DP, DQ, and DRB3/4/5 restricted responses showed that Dengue virus-specific CD4+ T cell responses were of lower magnitude compared to HLA-DRB1 (58,59). This is consistent with their lower levels of expression (58). Future studies should experimentally confirm the HLA-restriction of these EXP1 T cell epitopes and possibly evaluate restriction by HLA-DP or DQ molecules.…”

Section: Discussionmentioning

confidence: 93%

“…In this study we have only tested the binding to DRB-molecules, since they restrict the majority of class II responses (∼50%), but acknowledge that restrictions by HLA-DQ and DP molecules are also possible (58). One study examining the HLA-DP, DQ, and DRB3/4/5 restricted responses showed that Dengue virus-specific CD4+ T cell responses were of lower magnitude compared to HLA-DRB1 (58,59). This is consistent with their lower levels of expression (58).…”

Section: Discussionmentioning

confidence: 99%

Detection of EXP1-Specific CD4+ T Cell Responses Directed Against a Broad Range of Epitopes Including Two Promiscuous MHC Class II Binders During Acute Plasmodium falciparum Malaria

et al. 2020

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Background: T cells are thought to play a major role in conferring immunity against malaria. This study aimed to comprehensively define the breadth and specificity of the Plasmodium falciparum (P. falciparum)-specific CD4+ T cell response directed against the exported protein 1 (EXP1) in a cohort of patients diagnosed with acute malaria. Methods: Peripheral blood mononuclear cells of 44 patients acutely infected with P. falciparum, and of one patient infected with P. vivax, were stimulated and cultured in vitro with an overlapping set of 31 P. falciparum-specific 13-17-mer peptides covering the entire EXP1 sequence. EXP1-specific T cell responses were analyzed by ELISPOT and intracellular cytokine staining for interferon-γ production after re-stimulation with individual peptides. For further characterization of the epitopes, in silico and in vitro human leukocyte antigen (HLA) binding studies and fine mapping assays were performed. Results: We detected one or more EXP1-specific CD4+ T cell responses (mean: 1.09, range 0-5) in 47% (21/45) of our patients. Responses were directed against 15 of the 31 EXP1 peptides. Peptides EXP1-P13 (aa60-74) and P15 (aa70-85) were detected by 18% (n = 8) and 27% (n = 12) of the 45 patients screened. The optimal length, as well as the corresponding most likely HLA-restriction, of each of these two peptides was assessed. Interestingly, we also identified one CD4+ T cell response against peptide EXP1-P15 in a patient who was infected with P. vivax but not falciparum. Conclusions: This first detailed characterization of novel EXP1-specific T cell epitopes provides important information for future analysis with major histocompatibility complex-multimer technology as well as for immunomonitoring and vaccine design.

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“…HLA-DQ cell surface expression on CD4 + and CD8 + T cells has been documented in health [ 34 ] as well as in relation to both autoimmune conditions (for example T1D, CD and vitiligo) and infectious episodes [ 35 , 36 ]. Our observation that HLA-DQ cell surface MFI was decreased both with increasing number of autoantibodies (sAB) as well as with cumulative exposure (cAB) suggests that sAB and cAB play a role of mediator of the association between HLA-DQ2/8 and HLA-DQ cell surface expression measured by MFI.…”

Section: Discussionmentioning

confidence: 99%

Decreased HLA-DQ expression on peripheral blood cells in children with varying number of beta cell autoantibodies

Svärd

Maziarz

Ramelius

et al. 2020

Journal of Translational Autoimmunity

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The risk for type 1 diabetes is strongly associated with HLA-DQ and the appearance of beta cell autoantibodies against either insulin, glutamate decarboxylase (GAD65), insulinoma-associated protein-2 (IA-2), or zinc transporter 8 (ZnT8). Prolonged exposure to autoantibodies may be related to T cell exhaustion known to occur in chronic infections or autoimmune disorders. It was hypothesized that autoantibody exposure may affect HLA-DQ expression on peripheral blood cells and thereby contribute to T cell exhaustion thought to be associated with the pathogenesis of type 1 diabetes. The aim of this study was to determine whether autoantibody exposure as an expression of autoimmunity burden was related to peripheral blood cell HLA-DQ cell surface expression in either 1) a cross-sectional analysis or 2) cumulative as area under the trajectory of autoantibodies during long term follow-up in the Diabetes Prediction in Skåne (DiPiS) study. Children (n = 67), aged 10–15 years were analyzed for complete blood count, HLA-DQ cell surface median fluorescence intensity (MFI), autoantibody frequency, and HLA genotypes by Next Generation Sequencing. Decreased HLA-DQ cell surface MFI with an increasing number of autoantibodies was observed in CD16 + , CD14 + CD16 − , CD4 + and CD8 + cells but not in CD19 + cells and neutrophils. HLA-DQ cell surface MFI was associated with HLA-DQ2/8 in CD4 + T cells, marginally in CD14 + CD16 − monocytes and CD8 + T cells. These associations appeared to be related to autoimmunity burden. The results suggest that HLA-DQ cell surface expression was related to HLA and autoimmunity burden.

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Characterization of Magnitude and Antigen Specificity of HLA-DP, DQ, and DRB3/4/5 Restricted DENV-Specific CD4+ T Cell Responses

Cited by 36 publications

References 46 publications

Identification and characterization of CD4+ T cell epitopes after Shingrix vaccination

Identification and characterization of CD4+ T cell epitopes after Shingrix vaccination

Detection of EXP1-Specific CD4+ T Cell Responses Directed Against a Broad Range of Epitopes Including Two Promiscuous MHC Class II Binders During Acute Plasmodium falciparum Malaria

Decreased HLA-DQ expression on peripheral blood cells in children with varying number of beta cell autoantibodies

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