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

Martin Kolev, Erin E West, Natalia Kunz, Daniel Chauss, E Ashley Moseman, Jubayer Rahman, Tilo Freiwald, Maria L Balmer, Jonas Lötscher, Sarah Dimeloe, 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 McGavernSteven M Holland, Christoph Hess, Majid Kazemian, Behdad Afzali, Claudia Kemper

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)513-527.e8
JournalImmunity
Volume52
Issue number3
DOIs
Publication statusPublished - 17 Mar 2020

Keywords

  • 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

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