Single-Cell RNA Sequencing Reveals T Helper Cells Synthesizing Steroids De Novo to Contribute to Immune Homeostasis
Bidesh Mahata,
Xiuwei Zhang,
Aleksandra A. Kolodziejczyk,
Valentina Proserpio,
Liora Haim-Vilmovsky,
Angela E. Taylor,
Daniel Hebenstreit,
Felix A. Dingler,
Victoria Moignard,
Berthold Göttgens,
Wiebke Arlt,
Andrew N.J. McKenzie,
Sarah A. Teichmann
Affiliations
Bidesh Mahata
EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK
Xiuwei Zhang
EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK
Aleksandra A. Kolodziejczyk
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK
Valentina Proserpio
EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK
Liora Haim-Vilmovsky
EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK
Angela E. Taylor
Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK
Daniel Hebenstreit
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 OQH, UK
Felix A. Dingler
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 OQH, UK
Victoria Moignard
Department of Haematology, Cambridge Institute for Medical Research and Wellcome Trust and MRC Cambridge Stem Cell Institute, Hills Road, Cambridge CB2 0XY, UK
Berthold Göttgens
Department of Haematology, Cambridge Institute for Medical Research and Wellcome Trust and MRC Cambridge Stem Cell Institute, Hills Road, Cambridge CB2 0XY, UK
Wiebke Arlt
Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK
Andrew N.J. McKenzie
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 OQH, UK
Sarah A. Teichmann
EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK
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.