Diapedesis-Induced Integrin Signaling via LFA-1 Facilitates Tissue Immunity by Inducing Intrinsic Complement C3 Expression in Immune Cells

Research output: Contribution to journalArticlepeer-review


  • Martin Kolev
  • Erin E West
  • Natalia Kunz
  • Daniel Chauss
  • E Ashley Moseman
  • Jubayer Rahman
  • Tilo Freiwald
  • Maria L Balmer
  • Jonas Lötscher
  • Elizabeth C Rosser
  • Lucy R Wedderburn
  • Katrin D Mayer-Barber
  • Andrea Bohrer
  • Paul Lavender
  • Andrew Cope
  • Luopin Wang
  • Mariana J Kaplan
  • Niki M Moutsopoulos
  • Dorian McGavern
  • Steven M Holland
  • Christoph Hess
  • Majid Kazemian
  • Behdad Afzali
  • Claudia Kemper

Colleges, School and Institutes

External organisations

  • 1] Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA [2] National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts 01702, USA.
  • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  • National Institute of Neurological Disorders and Stroke (NINDS)
  • Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel and University of Basel, Basel, Switzerland.
  • Cancer Immunology and Immunotherapy Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.
  • University College London (UCL) Great Ormond Street Institute of Child Health
  • National Institute of Allergy and Infectious Diseases (NIAID)
  • King's Health Partners Cancer Biobank
  • Indiana University-Purdue University Indianapolis
  • National Institute of Arthritis and Musculoskeletal and Skin Disease (NIAMS)
  • National Institute of Dental and Craniofacial Research (NIDCR)
  • Fungal Pathogenesis Unit, Laboratory of Clinical Immunology and Microbiology, National Institutes of Health, Bethesda, MD 20892, USA. rebecca.drummond@nih.gov.
  • Cancer Research UK Cambridge Institute
  • Section for Functional Genetics, Institute of Human Genetics, University of Lübeck, Lübeck, Germany.


Intrinsic complement C3 activity is integral to human T helper type 1 (Th1) and cytotoxic T cell responses. Increased or decreased intracellular C3 results in autoimmunity and infections, respectively. The mechanisms regulating intracellular C3 expression remain undefined. We identified complement, including C3, as among the most significantly enriched biological pathway in tissue-occupying cells. We generated C3-reporter mice and confirmed that C3 expression was a defining feature of tissue-immune cells, including T cells and monocytes, occurred during transendothelial diapedesis, and depended on integrin lymphocyte-function-associated antigen 1 (LFA-1) signals. Immune cells from patients with leukocyte adhesion deficiency type 1 (LAD-1) had reduced C3 transcripts and diminished effector activities, which could be rescued proportionally by intracellular C3 provision. Conversely, increased C3 expression by T cells from arthritis patients correlated with disease severity. Our study defines integrins as key controllers of intracellular complement, demonstrates that perturbations in the LFA-1-C3-axis contribute to primary immunodeficiency, and identifies intracellular C3 as biomarker of severity in autoimmunity.

Bibliographic note

Copyright © 2020 Elsevier Inc. All rights reserved.


Original languageEnglish
Pages (from-to)513-527.e8
Issue number3
Publication statusPublished - 17 Mar 2020


  • Adult, Aged, Animals, Arthritis, Rheumatoid/immunology, Child, Child, Preschool, Complement C3/genetics, Female, Humans, Integrins/immunology, Lymphocyte Function-Associated Antigen-1/immunology, Lymphocytes/immunology, Male, Mice, Inbred C57BL, Middle Aged, Monocytes/immunology, Signal Transduction/immunology, Transendothelial and Transepithelial Migration/immunology