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Type I IFN Sensing by cDCs and CD4⁺ T Cell Help Are Both Requisite for Cross-Priming of AAV Capsid-Specific CD8⁺ T Cells.

ABSTRACT: Adeno-associated virus (AAV) vectors are widely used in clinical gene therapy to correct genetic disease by in vivo gene transfer. Although the vectors are useful, in part because of their limited immunogenicity, immune responses directed at vector components have complicated applications in humans. These include, for instance, innate immune sensing of vector components by plasmacytoid dendritic cells (pDCs), which sense the vector DNA genome via Toll-like receptor 9. Adaptive immune responses employ antigen presentation by conventional dendritic cells (cDCs), which leads to cross-priming of capsid-specific CD8⁺ T cells. In this study, we sought to determine the mechanisms that promote licensing of cDCs, which is requisite for CD8⁺ T cell activation. Blockage of type 1 interferon (T1 IFN) signaling by monoclonal antibody therapy prevented cross-priming. Furthermore, experiments in cell-type-restricted knockout mice showed a specific requirement for the receptor for T1 IFN (IFNaR) in cDCs. In contrast, natural killer (NK) cells are not needed, indicating a direct rather than indirect effect of T1 IFN on cDCs. In addition, co-stimulation by CD4⁺ T cells via CD40-CD40L was required for cross-priming, and blockage of co-stimulation but not of T1 IFN additionally reduced antibody formation against capsid. These mechanistic insights inform the development of targeted immune interventions.

SUBMITTER: Shirley JL

PROVIDER: S-EPMC7054715 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Type I IFN Sensing by cDCs and CD4<sup>+</sup> T Cell Help Are Both Requisite for Cross-Priming of AAV Capsid-Specific CD8<sup>+</sup> T Cells.

Shirley Jamie L JL Keeler Geoffrey D GD Sherman Alexandra A Zolotukhin Irene I Markusic David M DM Hoffman Brad E BE Morel Laurence M LM Wallet Mark A MA Terhorst Cox C Herzog Roland W RW

Molecular therapy : the journal of the American Society of Gene Therapy 20191115 3

Adeno-associated virus (AAV) vectors are widely used in clinical gene therapy to correct genetic disease by in vivo gene transfer. Although the vectors are useful, in part because of their limited immunogenicity, immune responses directed at vector components have complicated applications in humans. These include, for instance, innate immune sensing of vector components by plasmacytoid dendritic cells (pDCs), which sense the vector DNA genome via Toll-like receptor 9. Adaptive immune responses e ...[more]

PMID: 31780366

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Project description:Visceral leishmaniasis (VL) is a chronic and often fatal disease caused by protozoans of the genus Leishmania that affects millions of people worldwide. Patients with symptomatic VL have an impaired anti-Leishmania-specific CD4+ T-cell response, which is reversed after clinical cure. In contrast, the quality of the CD4+ and CD8+ T-cell responses involved in resistance and/or cure of VL relies on the capability of these cells to activate polyfunctional and memory responses, which are associated with the simultaneous production of three cytokines: IFN-γ, IL-2, and TNF-α. Models for the development of CD4 and CD8 T-cell quality in memory and protection to leishmaniasis have been described previously. We aimed to assess the functionality of the T cells involved in the recovery of the immune suppression throughout the VL treatment. Therefore, we cultured peripheral blood mononuclear cells (PBMCs) from VL patients and healthy controls in vitro with soluble Leishmania antigen (SLA). Cell surface markers and intracellular cytokine production were determined on days 7, 14, 21, 30, 60, 90, and 180 after the beginning of chemotherapy. We observed that the frequencies of CD4+TNF-α+IFN-γ+ and the multifunctional CD4+IL-2+TNF-α+IFN-γ+, together with CD4+TNF-α+ and CD4+IFN-γ+ T cells, increased throughout and at the end of the treatment, respectively. In addition, enhanced frequencies of CD8+IL-2+TNF-α+IFN-γ+ and CD8+TNF-α+IFN-γ T cells were also relevant in the healing process. Noteworthy, the frequencies of the CD4+ and CD8 central-memory T cells, which produce IL-2, TNF-α, and IFN-γ and ensure the memory response against parasite reinfection, are significantly enhanced in cured patients. In addition, the subset of the non-functional CD8Low population is predominant in VL untreated patients and decreases along the chemotherapy treatment. In contrast, a CD8High subset increased towards the cure. Furthermore, the cure due to treatment with meglumine antimoniate or with liposomal amphotericin B was associated with the recovery of the T-cell immune responses. We described the evolution and participation of functional T cells during the treatment of patients with VL. Our results disclosed that the clinical improvement of patients is significantly associated with the participation of the CD4+ and CD8+ cytokine-secreting T cells.

Dataset Information

Type I IFN Sensing by cDCs and CD4⁺ T Cell Help Are Both Requisite for Cross-Priming of AAV Capsid-Specific CD8⁺ T Cells.

Publications

Type I IFN Sensing by cDCs and CD4<sup>+</sup> T Cell Help Are Both Requisite for Cross-Priming of AAV Capsid-Specific CD8<sup>+</sup> T Cells.

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Dataset Information

Type I IFN Sensing by cDCs and CD4+ T Cell Help Are Both Requisite for Cross-Priming of AAV Capsid-Specific CD8+ T Cells.

Publications

Type I IFN Sensing by cDCs and CD4<sup>+</sup> T Cell Help Are Both Requisite for Cross-Priming of AAV Capsid-Specific CD8<sup>+</sup> T Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Type I IFN Sensing by cDCs and CD4⁺ T Cell Help Are Both Requisite for Cross-Priming of AAV Capsid-Specific CD8⁺ T Cells.