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Bone marrow-selected antigen specific regulatory B cells

ABSTRACT: Autoimmunity is often regarded as pathogenic, but this view has gradually shifted over time. Based on insights from thymus selection, T cells are now known to be selected by self-antigens and positive selection in the thymus medulla leads to regulatory functions. B cells are selected in the bone marrow and the fundamental question is whether self-antigens in the bone marrow select antigen specific regulatory B cells. In this work, we show that B cells are indeed selected for proteins expressed in the bone marrow and develop into cells with regulatory function bearing distinct phenotypic fingerprint. Collagen type II specific regulatory B cells trigger the expansion of antigen specific regulatory T cells and protect against development of tissue specific autoimmune inflammation. These antigen specific regulatory B cells constitute a sizeable fraction of the normal B cell repertoire in both mice and humans.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Spleen, B Cell

DISEASE(S): Arthritis

SUBMITTER: Christian Beusch

LAB HEAD: Rikard Holmdahl

PROVIDER: PXD025837 | Pride | 2023-08-13

REPOSITORIES: Pride

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Project description:Background Clinical success of T cell receptor (TCR) gene therapy has previously been demonstrated for NY-ESO-1 TCR gene therapy. To increase numbers of cancer patients that can be treated with TCR gene therapy we aimed to identify a novel set of high-affinity cancer specific TCRs targeting different cancer testis (CT) antigens in prevalent HLA class I alleles. Methods In this study, we selected based on publicly available gene expression databases the most promising CT genes to target. From these selected genes we identified by HLA peptidomics the naturally processed and presented HLA class I peptides. With these peptide-HLA tetramers were generated, and by single cell sorting CT specific CD8+ T cells were selected, and expanded from the allo-HLA repertoire of healthy donors. By several functional assays high avidity CT-specific T cell clones with safe recognition pattern were selected. To evaluate the potential for clinical application in TCR gene therapy, TCRs were sequenced and transferred into peripheral blood derived CD8+ T cells. Results In total we identified, 7 novel CT-specific TCRs that effectively target MAGE-A1, MAGE-A3, MAGE-A6 and MAGE-A9 in the context of human leukocyte antigen(HLA) -A1, -A2, -A3, -B7, -B35 and -C7. TCR gene transfer into CD8⁺ T cells resulted in efficient cytokine production and cytotoxicity of variety of different tumor types without detectable cross-reactivity. In addition, major in vivo antitumor effects of MAGE-A1 specific TCR engineered CD8⁺ T cells was observed in an orthotopic xenograft model for established multiple myeloma, in which bone marrow located tumor cells were completely eradicated after T cell injection. Conclusion The identification of 7 novel CT-specific TCRs, reactive against CT antigens presented in a variety of different HLA class I alleles, allows selection of therapeutic TCRs for an increased number of cancer patients, and will improve development of personalized TCR gene therapy.

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Bone marrow-selected antigen specific regulatory B cells

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