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Diverse Immunomodulatory Effects of Individual IFN? Subtypes on Virus-Specific CD8⁺ T Cell Responses.

ABSTRACT: Clinical administration of Interferon ? (IFN?) resulted in limited therapeutic success against some viral infections. Immune modulation of CD8⁺ T cell responses during IFN? therapy is believed to play a pivotal role in promoting viral clearance. However, these clinical studies primarily focused on IFN? subtype 2. To date, the immunomodulatory roles of the remaining 10-13 IFN? subtypes remains poorly understood, thereby precluding assessments of their potential for more effective treatments. Here, we report that virus-specific CD8⁺ T cell responses were influenced to various extents by individual IFN? subtypes. IFN?4, 6, and 9 had the strongest effects on CD8⁺ T cells, including antiproliferative effects, improved cytokine production and cytotoxicity. Interestingly, augmented cytokine responses were dependent on IFN? subtype stimulation of dendritic cells (DCs), while antiproliferative effects and cytotoxicity were mediated by IFNAR signaling in either CD8⁺ T cells or DCs. Thus, precise modulation of virus-specific CD8⁺ T cell responses may be feasible for specific antiviral immunotherapies through careful selection and administration of individual IFN? subtypes.

SUBMITTER: Dickow J

PROVIDER: S-EPMC6771563 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Diverse Immunomodulatory Effects of Individual IFNα Subtypes on Virus-Specific CD8<sup>+</sup> T Cell Responses.

Dickow Julia J Francois Sandra S Kaiserling Rouven-Luca RL Malyshkina Anna A Drexler Ingo I Westendorf Astrid Maria AM Lang Karl Sebastian KS Santiago Mario L ML Dittmer Ulf U Sutter Kathrin K

Frontiers in immunology 20190924

Clinical administration of Interferon α (IFNα) resulted in limited therapeutic success against some viral infections. Immune modulation of CD8<sup>+</sup> T cell responses during IFNα therapy is believed to play a pivotal role in promoting viral clearance. However, these clinical studies primarily focused on IFNα subtype 2. To date, the immunomodulatory roles of the remaining 10-13 IFNα subtypes remains poorly understood, thereby precluding assessments of their potential for more effective treat ...[more]

PMID: 31608062

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Project description:Background & aimsEndoplasmic reticulum aminopeptidase 1 (ERAP1) polymorphisms are linked with human leukocyte antigen (HLA) class I-associated autoinflammatory disorders, including ankylosing spondylitis and Behçet's disease. Disease-associated ERAP1 allotypes exhibit distinct functional properties, but it remains unclear how differential peptide trimming in vivo affects the repertoire of epitopes presented to CD8+ T cells. The aim of this study was to determine the impact of ERAP1 allotypes on the virus-specific CD8+ T cell epitope repertoire in an HLA-B*27:05+ individual with acute hepatitis C virus (HCV) infection.MethodsWe performed genetic and functional analyses of ERAP1 allotypes and characterized the HCV-specific CD8+ T cell repertoire at the level of fine epitope specificity and HLA class I restriction, in a patient who had acquired an HCV genotype 1a infection through a needle-stick injury.ResultsTwo hypoactive allotypic variants of ERAP1 were identified in an individual with acute HCV infection. The associated repertoire of virus-derived epitopes recognized by CD8+ T cells was uncommon in a couple of respects. Firstly, reactivity was directed away from classically immunodominant epitopes, preferentially targeting either novel or subdominant epitopes. Secondly, reactivity was biased towards longer epitopes (10-11-mers). Despite the patient exhibiting favorable prognostic indicators, these atypical immune responses failed to clear the virus and the patient developed persistent low-level infection with HCV.ConclusionsERAP1 allotypes modify the virus-specific CD8+ T cell epitope repertoire in vivo, leading to altered immunodominance patterns that may contribute to the failure of antiviral immunity after infection with HCV.Lay summaryEndoplasmic reticulum aminopeptidase 1 (ERAP1) plays a key role in antigen presentation. Genetic variants of ERAP1 (leading to distinct allotypes) are linked with specific autoinflammatory disorders, such as ankylosing spondylitis and Behçet's disease. We found that ERAP1 allotypes modified the repertoire of virus-specific CD8+ T cell epitopes in a patient with hepatitis C virus, leading to an altered pattern of immunodominance that may have contributed to the failure of antiviral immunity in this patient.

Dataset Information

Diverse Immunomodulatory Effects of Individual IFN? Subtypes on Virus-Specific CD8+ T Cell Responses.

Publications

Diverse Immunomodulatory Effects of Individual IFNα Subtypes on Virus-Specific CD8<sup>+</sup> T Cell Responses.

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Diverse Immunomodulatory Effects of Individual IFN? Subtypes on Virus-Specific CD8⁺ T Cell Responses.