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Single-Cell Transcriptional Analysis of Murine Mesenteric Lymph Nodes Following Oral Lyso-phosphatidylserine Nanoparticle Administration Reveals Cellular Heterogeneity in Tolerance Features

ABSTRACT: Unwanted immune responses against self-proteins or exogenous therapeutic proteins can trigger autoimmune diseases or compromise the safety and efficacy of life-saving therapeutic biologics. To address this issue, we utilized the ability of phosphatidylserine (PS) to convert an immunogen into a tolerogen and rationally developed a LysoPS-containing tolerogenic nanoparticle platform to prevent and mitigate unwanted immune responses. We demonstrated that prophylactic oral treatment with LysoPS-containing proteins prevents unwanted immune responses by inducing tolerance. However, the biological processes and cellular communication involved in LysoPS-mediated oral tolerance remain unclear. Therefore, this study aimed to characterize immune cell interactions and the potential tolerogenic mechanism in mice treated with LysoPS using Single-cell RNA sequencing (scRNA-seq). Our data showed that LysoPS nanoparticles increased the expression of RNAs associated with tolerogenic features in B cells, T cells, and NK cells, primarily through TGF-β responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE302907 | GEO | 2025/07/29

REPOSITORIES: GEO

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Project description:Dendritic cells (DCs) are mediators between innate and adaptive immunity and Q8 vital in initiating and modulating antigen-specific immune responses. The most important site for induction of tolerance is the gut mucosa, where TGF-b, retinoic acid, and aryl hydrocarbon receptors collaborate in DCs to induce a tolerogenic phenotype. To mimic this, a novel combination of compounds – the synthetic aryl hydrocarbon receptor (AhR) agonist IGN-512 together with TGF-b and retinoic acid – was developed to create a platform technology for induction of tolerogenic DCs intended for treatment of several conditions caused by unwanted immune activation. These in vitro-generated cells, designated ItolDCs, are phenotypically characterized by their low expression of costimulatory and activating molecules along with high expression of toleranceassociated markers such as ILT3, CD103, and LAP, and a weak pro-inflammatory cytokine profile. When co-cultured with T cells and/or B cells, ItolDC-cultures contain higher frequencies of CD25+Foxp3+ regulatory T cells (Tregs), CD49b +LAG3+ type 1 regulatory T (Tr1), and IL-10-producing B cells and are less T cell stimulatory compared to cultures with matured DCs. Factor VIII (FVIII) and tetanus toxoid (TT) were used as model antigens to study ItolDC antigenloading. ItolDCs can take up FVIII, process, and present FVIII peptides on HLADR. By loading both ItolDCs and mDCs with TT, antigen-specific T cell proliferation was observed. Cryo-preserved ItolDCs showed a stable tolerogenic phenotype that was maintained after stimulation with LPS, CD40L, or a pro-inflammatory cocktail. Moreover, exposure to other immune cells did 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 Frontiers in Immunology 01 frontiersin.org OPEN ACCESS EDITED BY Amy Rosenberg, EpiVax, United States REVIEWED BY Catharien Hilkens, Newcastle University, United Kingdom Dawn Elaine Smilek, UCSF, United States Q3 *CORRESPONDENCE Gillian Dao Nyesiga gillian.dao-nyesiga@mau.se RECEIVED 15 September 2022 ACCEPTED 25 August 2023 PUBLISHED xx xx 2023 CITATION Dao Nyesiga G, Pool L, Englezou PC, Hylander T, Ohlsson L, Appelgren D, Sundstedt A, Tillerkvist K, Romedahl HR and Wigren M (2023) Tolerogenic dendritic cells generated in vitro using a novel protocol mimicking mucosal tolerance mechanisms represent a potential therapeutic cell platform for induction of immune tolerance. Front. Immunol. 14:1045183. doi: 10.3389/fimmu.2023.1045183 COPYRIGHT © 2023 Dao Nyesiga, Pool, Englezou, Hylander, Ohlsson, Appelgren, Sundstedt, Tillerkvist, Romedahl and Wigren. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. TYPE Original Research PUBLISHED xx xx 2023 DOI 10.3389/fimmu.2023.1045183 not negatively impact ItolDCs’ expression of tolerogenic markers. In summary, a novel protocol was developed supporting the generation of a stable population of human DCs in vitro that exhibited a tolerogenic phenotype with an ability to increase proportions of induced regulatory T and B cells in mixed cultures.

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Single-Cell Transcriptional Analysis of Murine Mesenteric Lymph Nodes Following Oral Lyso-phosphatidylserine Nanoparticle Administration Reveals Cellular Heterogeneity in Tolerance Features

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