title: Single-cell RNA sequencing reveals T helper cells synthesizing steroids de novo to contribute to immune homeostasis.
abstract: T helper 2 (Th2) cells regulate helminth infections, allergic disorders, tumor immunity, and pregnancy by secreting various cytokines. It is likely that there are undiscovered Th2 signaling molecules. Although steroids are known to be immunoregulators, de novo steroid production from immune cells has not been previously characterized. Here, we demonstrate production of the steroid pregnenolone by Th2 cells in vitro and in vivo in a helminth infection model. Single-cell RNA sequencing and quantitative PCR analysis suggest that pregnenolone synthesis in Th2 cells is related to immunosuppression. In support of this, we show that pregnenolone inhibits Th cell proliferation and B cell immunoglobulin class switching. We also show that steroidogenic Th2 cells inhibit Th cell proliferation in a Cyp11a1 enzyme-dependent manner. We propose pregnenolone as a "lymphosteroid," a steroid produced by lymphocytes. We speculate that this de novo steroid production may be an intrinsic phenomenon of Th2-mediated immune responses to actively restore immune homeostasis.
authors.affiliation: EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 OQH, UK; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. Electronic address: bm11@sanger.ac.uk.
authors.forename: Bidesh
authors.initials: B
authors.lastname: Mahata
authors.affiliation: EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Xiuwei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Aleksandra A
authors.initials: AA
authors.lastname: Kolodziejczyk
authors.affiliation: EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 OQH, UK; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Valentina
authors.initials: V
authors.lastname: Proserpio
authors.affiliation: EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 OQH, UK; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Liora
authors.initials: L
authors.lastname: Haim-Vilmovsky
authors.affiliation: Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Angela E
authors.initials: AE
authors.lastname: Taylor
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 OQH, UK; School of Life Sciences, The University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hebenstreit
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 OQH, UK.
authors.forename: Felix A
authors.initials: FA
authors.lastname: Dingler
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research and Wellcome Trust and MRC Cambridge Stem Cell Institute, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Moignard
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research and Wellcome Trust and MRC Cambridge Stem Cell Institute, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
authors.affiliation: Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Arlt
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 OQH, UK.
authors.forename: Andrew N J
authors.initials: AN
authors.lastname: McKenzie
authors.affiliation: EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. Electronic address: st9@sanger.ac.uk.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Teichmann
mesh_terms: D000818:Animals; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011284:Pregnenolone / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D012313:RNA / Q000235:genetics / Q000378:metabolism*; D017423:Sequence Analysis, RNA / Q000379:methods; D059010:Single-Cell Analysis / Q000379:methods; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D059467:Transcriptome
chemical_list: D012313:RNA; D011284:Pregnenolone