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 McGavern; Steven M. Holland; Christoph Hess; Majid Kazemian; Behdad Afzali; Claudia Kemper

doi:10.1016/j.immuni.2020.02.006

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

^*Corresponding author for this work

Institute of Systemic Inflamation Research

4 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 language	English
Journal	Immunity
Volume	52
Issue number	3
Pages (from-to)	513-527.e8
ISSN	1074-7613
DOIs	https://doi.org/10.1016/j.immuni.2020.02.006
Publication status	Published - 17.03.2020

Funding

We thank the patients and the healthy donors for their support. This work was financed by MRC Centre grant MR/J006742/1 ; an EU -funded Innovative Medicines Initiative BTCURE (C.K.); a Wellcome Trust Investigator Award (grant 102932/Z/13/Z to C.K); a Wellcome Trust Intermediate Clinical Fellowship (grant 097261/Z/11/Z to B.A.); the National Heart, Lung, and Blood Institute of the NIH (grant 5K22HL125593 to M. Kazemian); a grant from the Guy's and St Thomas' Charity (C.K. and B.A.); the National Institute for Health Research ( NIHR ) Biomedical Research Centre at Great Ormond Street NHS Foundation Trust (L.R.W. and L.R.); The King’s College London BRC Genomics Facility ; the NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King’s College London ; SNSF funding to C.H. ( 31003A_172848 ); and in part by the Intramural Research Program of the NIH , the National Institute of Diabetes and Digestive and Kidney Diseases (project number ZIA/DK075149 to B.A.), and the National Heart, Lung, and Blood Institute (project number zia/hl006223 to C.K.).

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.immuni.2020.02.006

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Kolev, M., West, E. E., Kunz, N., Chauss, D., Moseman, E. A., Rahman, J., Freiwald, T., Balmer, M. L., Lötscher, J., Dimeloe, S., Rosser, E. C., Wedderburn, L. R., Mayer-Barber, K. D., Bohrer, A., Lavender, P., Cope, A., Wang, L., Kaplan, M. J., Moutsopoulos, N. M., ... Kemper, C. (2020). Diapedesis-Induced Integrin Signaling via LFA-1 Facilitates Tissue Immunity by Inducing Intrinsic Complement C3 Expression in Immune Cells. Immunity, 52(3), 513-527.e8. https://doi.org/10.1016/j.immuni.2020.02.006

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

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.",

author = "Martin Kolev and West, {Erin E.} and Natalia Kunz and Daniel Chauss and Moseman, {E. Ashley} and Jubayer Rahman and Tilo Freiwald and Balmer, {Maria L.} and Jonas L{\"o}tscher and Sarah Dimeloe and Rosser, {Elizabeth C.} and Wedderburn, {Lucy R.} and Mayer-Barber, {Katrin D.} and Andrea Bohrer and Paul Lavender and Andrew Cope and Luopin Wang and Kaplan, {Mariana J.} and Moutsopoulos, {Niki M.} and Dorian McGavern and Holland, {Steven M.} and Christoph Hess and Majid Kazemian and Behdad Afzali and Claudia Kemper",

note = "Funding Information: We thank the patients and the healthy donors for their support. This work was financed by MRC Centre grant MR/J006742/1 ; an EU -funded Innovative Medicines Initiative BTCURE (C.K.); a Wellcome Trust Investigator Award (grant 102932/Z/13/Z to C.K); a Wellcome Trust Intermediate Clinical Fellowship (grant 097261/Z/11/Z to B.A.); the National Heart, Lung, and Blood Institute of the NIH (grant 5K22HL125593 to M. Kazemian); a grant from the Guy's and St Thomas' Charity (C.K. and B.A.); the National Institute for Health Research ( NIHR ) Biomedical Research Centre at Great Ormond Street NHS Foundation Trust (L.R.W. and L.R.); The King{\textquoteright}s College London BRC Genomics Facility ; the NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King{\textquoteright}s College London ; SNSF funding to C.H. ( 31003A_172848 ); and in part by the Intramural Research Program of the NIH , the National Institute of Diabetes and Digestive and Kidney Diseases (project number ZIA/DK075149 to B.A.), and the National Heart, Lung, and Blood Institute (project number zia/hl006223 to C.K.). Publisher Copyright: {\textcopyright} 2020 Elsevier Inc. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = mar,

day = "17",

doi = "10.1016/j.immuni.2020.02.006",

language = "English",

volume = "52",

pages = "513--527.e8",

journal = "Immunity",

issn = "1074-7613",

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number = "3",

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Kolev, M, West, EE, Kunz, N, Chauss, D, Moseman, EA, Rahman, J, Freiwald, T, Balmer, ML, Lötscher, J, Dimeloe, S, Rosser, EC, Wedderburn, LR, Mayer-Barber, KD, Bohrer, A, Lavender, P, Cope, A, Wang, L, Kaplan, MJ, Moutsopoulos, NM, McGavern, D, Holland, SM, Hess, C, Kazemian, M, Afzali, B & Kemper, C 2020, 'Diapedesis-Induced Integrin Signaling via LFA-1 Facilitates Tissue Immunity by Inducing Intrinsic Complement C3 Expression in Immune Cells', Immunity, vol. 52, no. 3, pp. 513-527.e8. https://doi.org/10.1016/j.immuni.2020.02.006

TY - JOUR

T1 - Diapedesis-Induced Integrin Signaling via LFA-1 Facilitates Tissue Immunity by Inducing Intrinsic Complement C3 Expression in Immune Cells

AU - Kolev, Martin

AU - West, Erin E.

AU - Kunz, Natalia

AU - Chauss, Daniel

AU - Moseman, E. Ashley

AU - Rahman, Jubayer

AU - Freiwald, Tilo

AU - Balmer, Maria L.

AU - Lötscher, Jonas

AU - Dimeloe, Sarah

AU - Rosser, Elizabeth C.

AU - Wedderburn, Lucy R.

AU - Mayer-Barber, Katrin D.

AU - Bohrer, Andrea

AU - Lavender, Paul

AU - Cope, Andrew

AU - Wang, Luopin

AU - Kaplan, Mariana J.

AU - Moutsopoulos, Niki M.

AU - McGavern, Dorian

AU - Holland, Steven M.

AU - Hess, Christoph

AU - Kazemian, Majid

AU - Afzali, Behdad

AU - Kemper, Claudia

N1 - Funding Information: We thank the patients and the healthy donors for their support. This work was financed by MRC Centre grant MR/J006742/1 ; an EU -funded Innovative Medicines Initiative BTCURE (C.K.); a Wellcome Trust Investigator Award (grant 102932/Z/13/Z to C.K); a Wellcome Trust Intermediate Clinical Fellowship (grant 097261/Z/11/Z to B.A.); the National Heart, Lung, and Blood Institute of the NIH (grant 5K22HL125593 to M. Kazemian); a grant from the Guy's and St Thomas' Charity (C.K. and B.A.); the National Institute for Health Research ( NIHR ) Biomedical Research Centre at Great Ormond Street NHS Foundation Trust (L.R.W. and L.R.); The King’s College London BRC Genomics Facility ; the NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King’s College London ; SNSF funding to C.H. ( 31003A_172848 ); and in part by the Intramural Research Program of the NIH , the National Institute of Diabetes and Digestive and Kidney Diseases (project number ZIA/DK075149 to B.A.), and the National Heart, Lung, and Blood Institute (project number zia/hl006223 to C.K.). Publisher Copyright: © 2020 Elsevier Inc. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/3/17

Y1 - 2020/3/17

N2 - 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.

AB - 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.

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U2 - 10.1016/j.immuni.2020.02.006

DO - 10.1016/j.immuni.2020.02.006

M3 - Journal articles

C2 - 32187519

AN - SCOPUS:85081269262

SN - 1074-7613

VL - 52

SP - 513-527.e8

JO - Immunity

JF - Immunity

IS - 3

ER -

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

Abstract

Funding

Research Areas and Centers

UN SDGs

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