Diapedesis facilitates tissue immunity by inducing immune cell-intrinsic complement C3 expression

Martin Kolev, Erin West, Natalia Kunz, Daniel Chauss, Ashley Moseman, Jubayer Rahman, Tilo Freiwald, Maria Balmer, Jonas Lötscher, Sarah Dimeloe, Elizabeth Rosser, Lucy Wedderburn, Paul Lavender, Andrew Cope, Luopin Wang, Mariana Kaplin, Niki Moutsopoulos, Dorian McGavern, Steven Holland, Christoph HessMajid Kazemian, Claudia Kemper, Behdad Afzali

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Abstract

Intracellularly generated, autocrine-functioning, complement C3 is integral to human Th1 and cytotoxic CD8+ T cell responses. Increased or decreased intracellular C3 result in autoimmunity and infections, respectively. The mechanisms regulating intracellular C3 expression are, however, undefined. By comparing transcriptomes of human immune cells from blood and tissues, we identified complement, including C3, as one of the most significantly enriched biological pathway in tissue-occupying cells. Utilizing a novel C3 reporter mouse, we confirmed that C3 expression is a defining feature of immune cells in tissues, occurs during trans-endothelial diapedesis and is dependent on integrin intercellular adhesion molecule (ICAM)-1 liganding lymphocyte function-associated antigen (LFA)-1. Consequently, immune cells from patients with leukocyte adhesion deficiency (LAD)-1 had reduced C3 and diminished effector activities, which could be rescued proportionally by normalization of intracellular C3. In synovia of patients with rheumatoid arthritis (RA), C3 expression by T cells was associated with disease severity and acted as a biomarker distinguishing inflamed versus uninflamed RA. Our study defines integrins as novel and key controllers of intracellular complement, demonstrates that perturbations in the LFA-1-C3 axis contribute to primary human immunodeficiency and identifies intracellular C3 as a biomarker of severity in autoimmunity.
Original languageEnglish
JournalImmunity
Publication statusAccepted/In press - 30 Jan 2020

Keywords

  • Intracellular complement, complosome, T cells, LFA-1, ICAM-1, integrins, metabolism, Th1 cells, lymphocyte adhesion deficiency type 1, LAD-1

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