CRELD1 modulates homeostasis of the immune system in mice and humans

  • Nat Immunol. 2020 Dec;21(12):1517-1527. doi: 10.1038/s41590-020-00811-2.
Lorenzo Bonaguro  1  2 ,  Maren Köhne  1  3 ,  Lisa Schmidleithner  1  3 ,  Jonas Schulte-Schrepping  1 ,  Stefanie Warnat-Herresthal  1 ,  Arik Horne  1 ,  Paul Kern  2  4 ,  Patrick Günther  1 ,  Rob Ter Horst  5 ,  Martin Jaeger  5 ,  Souad Rahmouni  6 ,  Michel Georges  6 ,  Christine S Falk  7 ,  Yang Li  5  8 ,  Elvira Mass  4 ,  Marc Beyer  1  3 ,  Leo A B Joosten  5 ,  Mihai G Netea  5  9 ,  Thomas Ulas  1  10 ,  Joachim L Schultze  1  10 ,  Anna C Aschenbrenner  11  12
Affiliations
  • 1. Genomics and Immunoregulation, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.
  • 2. Developmental Genetics & Molecular Physiology, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.
  • 3. Molecular Immunology in Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
  • 4. Developmental Biology of the Innate Immune System, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.
  • 5. Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands.
  • 6. Unit of Animal Genomics, GIGA-Institute, University of Liège, Liège, Belgium.
  • 7. Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany.
  • 8. Department of Computational Biology for Individualised Infection Medicine, Centre for Individualised Infection Medicine (CiiM) & TWINCORE, joint ventures between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany.
  • 9. Immunology & Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany.
  • 10. German Center for Neurodegenerative Diseases (DZNE), PRECISE Platform for Single Cell Genomics and Epigenomics at the DZNE and the University of Bonn, Bonn, Germany.
  • 11. Genomics and Immunoregulation, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany. [email protected].
  • 12. Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands. [email protected].
PMID: 33169013 DOI: 10.1038/s41590-020-00811-2
Abstract

CRELD1 is a pivotal factor for heart development, the function of which is unknown in adult life. We here provide evidence that CRELD1 is an important gatekeeper of immune system homeostasis. Exploiting expression variance in large human cohorts contrasting individuals with the lowest and highest CRELD1 expression levels revealed strong phenotypic, functional and transcriptional differences, including reduced CD4+ T cell numbers. These findings were validated in T cell-specific Creld1-deficient mice. Loss of Creld1 was associated with simultaneous overactivation and increased Apoptosis, resulting in a net loss of T cells with age. Creld1 was transcriptionally and functionally linked to Wnt signaling. Collectively, gene expression variance in large human cohorts combined with murine genetic models, transcriptomics and functional testing defines CRELD1 as an important modulator of immune homeostasis.

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