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Interferon-α promotes neo-antigen formation and preferential HLA-B-restricted antigen presentation in pancreatic β-cells.

ABSTRACT: Interferon (IFN)-α is the earliest cytokine signature observed in individuals at risk for type 1 diabetes (T1D), but its effect on the repertoire of HLA Class I (HLA-I)-bound peptides presented by pancreatic β-cells is unknown. Using immunopeptidomics, we characterized the peptide/HLA-I presentation in in-vitro resting and IFN-α-exposed β-cells. IFN-α increased HLA-I expression and peptide presentation, including neo-sequences derived from alternative mRNA splicing, post-translational modifications - notably glutathionylation - and protein cis-splicing. This antigenic landscape relied on processing by both the constitutive and immune proteasome. The resting β-cell immunopeptidome was dominated by HLA-A-restricted ligands. However, IFN-α only marginally upregulated HLA-A and largely favored HLA-B, translating into a major increase in HLA-B-restricted peptides and into an increased activation of HLA-B-restricted vs. HLA-A-restricted CD8⁺ T-cells. A preferential HLA-B hyper-expression was also observed in the islets of T1D vs. non-diabetic donors, and we identified islet-infiltrating CD8⁺ T-cells from T1D donors reactive to HLA-B-restricted granule peptides. Thus, the inflammatory milieu of insulitis may skew the autoimmune response toward epitopes presented by HLA-B, hence recruiting a distinct T-cell repertoire that may be relevant to T1D pathogenesis.

SUBMITTER: Carre A

PROVIDER: S-EPMC10516036 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Interferon-α promotes neo-antigen formation and preferential HLA-B-restricted antigen presentation in pancreatic β-cells.

Carré Alexia A Zhou Zhicheng Z Perez-Hernandez Javier J Samassa Fatoumata F Lekka Christiana C Manganaro Anthony A Oshima Masaya M Liao Hanqing H Parker Robert R Nicastri Annalisa A Brandao Barbara B Colli Maikel L ML Eizirik Decio L DL Göransson Marcus M Morales Orlando Burgos OB Anderson Amanda A Landry Laurie L Kobaisi Farah F Scharfmann Raphael R Marselli Lorella L Marchetti Piero P You Sylvaine S Nakayama Maki M Hadrup Sine R SR Kent Sally C SC Richardson Sarah J SJ Ternette Nicola N Mallone Roberto R

bioRxiv : the preprint server for biology 20230917

Interferon (IFN)-α is the earliest cytokine signature observed in individuals at risk for type 1 diabetes (T1D), but its effect on the repertoire of HLA Class I (HLA-I)-bound peptides presented by pancreatic β-cells is unknown. Using immunopeptidomics, we characterized the peptide/HLA-I presentation in <i>in-vitro</i> resting and IFN-α-exposed β-cells. IFN-α increased HLA-I expression and peptide presentation, including neo-sequences derived from alternative mRNA splicing, post-translational mod ...[more]

PMID: 37745505

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Project description:Human-restricted Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of typhoid fever-a life-threatening disease of great global health significance, particularly in the developing world. Ty21a is an oral live-attenuated vaccine that protects against the development of typhoid disease in part by inducing robust T cell responses, among which multifunctional CD8+ cytotoxic T lymphocytes (CTL) play an important role. Following Ty21a vaccination, a significant component of adult CTL have shown to be targeted to S. Typhi antigen presented by the conserved major histocompatibility complex (MHC) class Ib molecule, human leukocyte antigen-E (HLA-E). S. Typhi challenge studies have shown that baseline, multifunctional HLA-E responsive T cells are associated with protection from, and delayed onset of, typhoid disease. However, despite the overwhelming burden of typhoid fever in school-aged children, and due to limited availability of pediatric samples, incomplete information is available regarding these important HLA-E-restricted responses in children, even though studies have shown that younger children may be less likely to develop protective cell mediated immune (CMI) responses than adults following vaccination. To address this gap, we have studied this phenomenon in depth by using mass cytometry to analyze pediatric and adult T cell responses to HLA-E-restricted S. Typhi antigen presentation, before and after Ty21a vaccination. Herein, we show variable responses in all age strata following vaccination among T effector memory (TEM) and T effector memory CD45RA+ (TEMRA) cells based on conventional gating analysis. However, by utilizing the dimensionality reduction tool tSNE (t-distributed Stochastic Neighbor Embedding), we are able to identify diverse, highly multifunctional gut-homing- TEM and TEMRA clusters of cells which are more abundant in adult and older pediatric participants than in younger children. These findings highlight a potential age-associated maturation of otherwise conserved HLA-E restricted T cell responses. Such insights, coupled with the marked importance of multifunctional T cell responses to combat infection, may better inform future pediatric vaccination strategies against S. Typhi and other infectious diseases.

Dataset Information

Interferon-α promotes neo-antigen formation and preferential HLA-B-restricted antigen presentation in pancreatic β-cells.

Publications

Interferon-α promotes neo-antigen formation and preferential HLA-B-restricted antigen presentation in pancreatic β-cells.

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