Involvement and prognosis value of CD8 + T cells in giant cell arteritis

Background:Giant cell arteritis (GCA) is the most frequent form of systemic vasculitis affecting the large- and medium-sized vessels. The involvement of innate immune cells and CD4+ T cells in the pathogenesis of GCA has been extensively studied. Interestingly, recent findings suggest a role for CD8+ T cells in disease development (1). However, CD8+ subsets and their functional capacities have not yet been studied in detail.Objectives:This study aims to characterize the phenotype and proliferative capacity of CD8+ T cells in newly diagnosed GCA patients and GCA patients in remission compared to healthy age- and sex- matched controls.Methods:To determine the phenotype of CD8+ T cells in GCA, newly diagnosed, untreated GCA patients (baseline, n=14), GCA patients in stable glucocorticoid-free remission (GC-FR, n=10) and age- and sex-matched healthy controls (HCs, n=18) were enrolled. Peripheral blood mononuclear cells (PBMCs) were stained with fluorochrome-conjugated antibodies directed against CD3, CD4, CD8, CCR7, CD45RO, Ki-67, CD69 and CD25 and analyzed by flow cytometry. The following differentiation subsets were defined: CD8+ T naive (CD45RO-CCR7+), central memory (TCM, CD45RO+CCR7+), effector memory (TEM, CD45RO+CCR7-) and effector memory re-expressing CD45RA (TEMRA, CD45RO-CCR7-) cells. Secondly, the proliferative capacity of CD8+ T cells was determined in isolated CD3+ T cells of 10 GCA baseline, 10 GCA GC-FR patients and 19 HCs after 5 days of stimulation with plate-bound anti-CD3 or anti-CD3 plus soluble anti-CD28 using a dye-based proliferation assay.Results:A reduced frequency of CD8+ TEMcells was found in GCA baseline patients compared to HCs (p=0.025). Furthermore, a higher frequency of Ki-67+ cells was detected among CD8+ TEMcells in GCA baseline patients than in HCs (p=0.0007), suggesting a higher proliferative activityin vivo.In addition,in vitrostimulation with anti-CD3 and anti-CD3+anti-CD28 led to higher percentages of divided CD8+ T cells in GCA baseline and GC-FR patients than in HCs (p<0.05). Moreover, the frequencies of CD8+ TEMRAcells and the percentage of divided CD8+ T cells upon CD3 stimulation strongly correlated in GCA baseline patients (R=0.79, p=0.009) and GCA GC-FR patients (R=0.67, p=0.039) but not in HCs (R=0.31, p=0.25).Conclusion:GCA baseline patients demonstrate a higher frequency of proliferating circulating CD8+ TEMcells, defined by Ki-67 expression, than HCs. In addition, functional data on induced proliferative capacity suggest that CD8+ T cells from GCA baseline patients are more rapidly activated by crosslinking CD3 and CD3+CD28, suggesting either reduced regulation in these patients or more intrinsic threshold changes. Furthermore, the induced proliferative capacity is also elevated in patients in stable glucocorticoid-free remission. Whether the increased proliferative capacity of total CD8+ T cells in GCA patients is causally linked to the increased frequencies of CD8+ TEMRAcells in these patients requires further investigation.References:[1]Samson M, Ly KH, Tournier B, Janikashvili N, Trad M, Ciudad M, et al. Involvement and prognosis value of CD8+ T cells in giant cell arteritis. J Autoimmun. 2016;72:73–83.Disclosure of Interests:Rosanne Reitsema: None declared, Rebeca Hid Cadena: None declared, Wayel Abdulahad: None declared, Annemieke Boots Consultant of: Grünenthal Gmbh until 2017, Peter Heeringa: None declared, Elisabeth Brouwer Consultant of: Roche (consultancy fee 2017 and 2018 paid to the UMCG), Speakers bureau: Roche (2017 and 2018 paid to the UMCG)

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Circulating CD8+ T cells in polymyalgia rheumatica and giant cell arteritis: A review

Seminars in Arthritis and Rheumatism ◽

10.1053/sarh.2001.9734 ◽

2001 ◽

Vol 30 (4) ◽

pp. 257-271 ◽

Cited By ~ 10

Author(s):

Victor M. Martinez-Taboada ◽

Ricardo Blanco ◽

Concepción Fito ◽

Maria Jose Bartolome Pacheco ◽

Miguel Delgado-Rodriguez ◽

...

Keyword(s):

T Cells ◽

Giant Cell Arteritis ◽

Giant Cell ◽

Cd8 T Cells ◽

Polymyalgia Rheumatica

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Clonally Expanded CD8 T Cells in Patients with Polymyalgia Rheumatica and Giant Cell Arteritis

Clinical Immunology and Immunopathology ◽

10.1006/clin.1996.0078 ◽

1996 ◽

Vol 79 (3) ◽

pp. 263-270 ◽

Cited By ~ 28

Author(s):

Victor M. Martinez-Taboada ◽

Jörg J. Goronzy ◽

Cornelia M. Weyand

Keyword(s):

T Cells ◽

Giant Cell Arteritis ◽

Giant Cell ◽

Cd8 T Cells ◽

Polymyalgia Rheumatica

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Mucosal-associated invariant T cells in Giant Cell Arteritis

Journal of Autoimmunity ◽

10.1016/j.jaut.2021.102652 ◽

2021 ◽

Vol 121 ◽

pp. 102652

Author(s):

Thibault Ghesquière ◽

Marion Ciudad ◽

André Ramon ◽

Hélène Greigert ◽

Claire Gerard ◽

...

Keyword(s):

T Cells ◽

Giant Cell Arteritis ◽

Giant Cell ◽

Invariant T Cells

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FRI0010 GM-CSFR PATHWAY IS IMPLICATED IN PATHOGENIC INFLAMMATORY MECHANISMS IN GIANT CELL ARTERITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.4984 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 576.1-576

Author(s):

M. C. Cid ◽

S. Muralidharan ◽

M. Corbera-Bellalta ◽

G. Espigol-Frigole ◽

J. Marco Hernandez ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mrna Expression ◽

Giant Cell Arteritis ◽

Giant Cell ◽

Signaling Pathway ◽

Ex Vivo ◽

Cell Marker ◽

Gm Csf ◽

Inflammatory Macrophages

Background:Giant Cell Arteritis (GCA) is characterized by inflammation of large and medium arteries. Classic symptoms include headaches, malaise and, in severe cases, blindness and aortic aneurysms. Corticosteroids (CS) are the first line of treatment. Relapsing disease patients undergo multiple courses of CS therapy increasing their CS exposure and toxicity. A significant unmet need for disease-modifying CS-sparing therapy remains in GCA as the efficacy of current treatment options, including tocilizumab have limitations.We have previously reported elevated expression of granulocyte-macrophage colony stimulating factor (GM-CSF) pathway transcriptomic signature in GCA vessels. GM-CSF may contribute to underlying disease mechanisms by regulating inflammatory macrophages, dendritic cells (DCs) and T helper (TH1/TH17) cells which are involved in GCA pathogenesis. GM-CSF produced by T cells1can promote polarization of inflammatory macrophages2and recruitment and differentiation of monocytes into inflammatory DCs2that can in turn recruit T cells and stimulate TH1/TH17 differentiation creating a feedback loop. GM-CSF may also exert direct effects on angiogenesis3and vessel wall remodeling4.Objectives:To demonstrate the contributing role of GM-CSF pathway to inflammation in GCA arteries.Methods:Immunostaining was used to examine expression of GM-CSF and GM-CSF-Rα proteins in temporal artery biopsies (TABs) from GCA and controls (patients with suspected but not confirmed GCA and a negative TAB). Costaining with cell markers such as CD31, CD3, and CD68 allowed visualization of cells expressing GM-CSF and GM-CSF-Rα. Expression of GM-CSF pathway molecules such as phospho-JAK2 and PU.1 proteins was detected by immunohistochemical staining of GCA and control TABs.Ex vivocultured GCA arteries treated (10 each) with mavrilimumab (anti-GM-CSF-Rα) or placebo for 5 days were assayed for gene expression by qPCR, and culture supernatants were analyzed by ELISA.Results:Endothelial cells and macrophages were the main cell types expressing GM-CSF and GM-CSF-Rα. Increased expression of phospho-JAK2 (activated signaling molecule) and nuclear-localized PU.1 (transcription factor) in GCA TABs compared to controls indicated the presence of active GM-CSF signaling pathway in GCA.Inhibition of PU.1 mRNA expression inex vivocultures of GCA arteries treated with mavrilimumab indicated blockade of GM-CSFR signaling pathway. Mavrilimumab induced decrease in mRNA expression of key cell type markers including DC and macrophage activation markers CD83 and HLA-DRA, monocyte markers CD14 and CD16, T cell marker CD3ε, and B cell marker CD20 in these GCA artery cultures. Expression of inflammatory TH1/TH17 factors IFNγ (mRNA), TNFα, CXCL10 (IFNγ-stimulated chemokine) and IL-6 (mRNA and protein) was also inhibited by mavrilimumab in GCA artery cultures.Conclusion:Increased GM-CSF, GM-CSF-Rα, and downstream pathway-associated protein levels in GCA biopsies were consistent with previously-observed increased transcriptome signature. Expression of genes associated with inflammatory cells was suppressed by mavrilimumab in cultured GCA arteries. These data implicate the GM-CSF pathway in GCA pathophysiology and increase confidence in rationale for targeting the GM-CSF pathway in GCA.References:[1]GM-CSF and T-cell responses: what we do and don’t know. Shiet al., Cell Res 2006[2]GM-CSF-Dependent Inflammatory Pathways. Hamilton, Front Immunol 2019[3]GM-CSF increases tumor growth and angiogenesis. Zhenget al., Tumour Biol 2017[4]GM-CSF deficiency affects vascular elastin production and integrity of elastic lamellae. Weissen-Plenzet al., J Vasc Res 2008Disclosure of Interests:Maria C. Cid Grant/research support from: Kiniksa Pharmaceuticals, Consultant of: Janssen, Abbvie, Roche, GSK, Speakers bureau: Vifor, Sujatha Muralidharan Shareholder of: Kiniksa, Employee of: Kiniksa, Marc Corbera-Bellalta: None declared, Georgina Espigol-Frigole Consultant of: Roche and Janssen, Javier Marco Hernandez: None declared, Amanda Denuc: None declared, Roberto Rios-Garces: None declared, Nekane Terrades-Garcia: None declared, John F. Paolini Shareholder of: Kiniksa, Employee of: Kiniksa, Annalisa D’Andrea Shareholder of: Kiniksa, Employee of: Kiniksa

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Distinct vascular lesions in giant cell arteritis share identical T cell clonotypes.

Journal of Experimental Medicine ◽

10.1084/jem.179.3.951 ◽

1994 ◽

Vol 179 (3) ◽

pp. 951-960 ◽

Cited By ~ 115

Author(s):

C M Weyand ◽

J Schönberger ◽

U Oppitz ◽

N N Hunder ◽

K C Hicok ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Giant Cell Arteritis ◽

Giant Cell ◽

Gene Segment ◽

Interleukin 2 ◽

Granulomatous Inflammation ◽

Temporal Artery ◽

Cell Receptor ◽

Vascular Lesions

Giant cell arteritis (GCA) is a spontaneous vasculitic syndrome that specifically targets the walls of medium and large arteries. Vascular lesions are characterized by patchy granulomatous infiltrates composed of T cells, macrophages, histiocytes, and giant cells. To test the hypothesis that a locally residing antigen recruits T cells into the vessel walls, we have analyzed T cell receptor (TCR) molecules of tissue infiltrating T cells. A total of 638 CD4+ T cell clones were isolated from temporal artery specimens of three patients with GCA. Analysis of TCR molecules for the usage of V beta 1-V beta 20 revealed that all TCR V beta elements were represented, demonstrating that interleukin 2 (IL-2)-responsive T cells infiltrating the tissue are highly diverse. To detect expanded T cell specificities, we made use of the patchy character of the inflammatory disease and compared the TCR repertoire of T cells established from independent vasculitic foci of the same artery. Sequence analysis of TCR V beta chains documented that individual TCR specificities were present in multiple copies, indicating clonal expansion. T cells with identical beta chains were isolated from distinct inflammatory foci of the same patient. These specificities represented only a small fraction of tissue-infiltrating T cells and involved the V beta 5.3 gene segment in the two patients sharing the HLA-DRB1*0401 allele. The third complementarity determining region of clonally expanded TCR beta chains was characterized by a cluster of negatively and positively charged residues, suggesting that the juxtaposed antigenic peptide is charged. The sharing of identical T cell specificities by distinct and independent regions of the granulomatous inflammation suggests that these T cells are disease relevant and that their repertoire is strongly restricted. These data suggest that an antigen residing in the arterial wall is recognized by a small fraction of CD4+ T cells in the inflammatory process characteristic for GCA.

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Activation of Arterial Wall Dendritic Cells and Breakdown of Self-tolerance in Giant Cell Arteritis

Journal of Experimental Medicine ◽

10.1084/jem.20030850 ◽

2004 ◽

Vol 199 (2) ◽

pp. 173-183 ◽

Cited By ~ 153

Author(s):

Wei Ma-Krupa ◽

Myung-Shin Jeon ◽

Silvia Spoerl ◽

Thomas F. Tedder ◽

Jörg J. Goronzy ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Giant Cell Arteritis ◽

Giant Cell ◽

Scid Mouse ◽

Severe Combined Immunodeficiency ◽

Medium Size ◽

Early Event ◽

Mouse Chimeras

Giant cell arteritis (GCA) is a granulomatous and occlusive vasculitis that causes blindness, stroke, and aortic aneurysm. CD4+ T cells are selectively activated in the adventitia of affected arteries. In human GCA artery–severe combined immunodeficiency (SCID) mouse chimeras, depletion of CD83+ dendritic cells (DCs) abrogated vasculitis, suggesting that DCs are critical antigen-presenting cells in GCA. Healthy medium-size arteries possessed an indigenous population of DCs at the adventitia–media border. Adoptive T cell transfer into temporal artery–SCID mouse chimeras demonstrated that DCs in healthy arteries were functionally immature, but gained T cell stimulatory capacity after injection of lipopolysaccharide. In patients with polymyalgia rheumatica (PMR), a subclinical variant of GCA, adventitial DCs were mature and produced the chemokines CCL19 and CCL21, but vasculitic infiltrates were lacking. Human histocompatibility leukocyte antigen class II–matched healthy arteries, PMR arteries, and GCA arteries were coimplanted into SCID mice. Immature DCs in healthy arteries failed to stimulate T cells, but DCs in PMR arteries could attract, retain, and activate T cells that originated from the GCA lesions. We propose that in situ maturation of DCs in the adventitia is an early event in the pathogenesis of GCA. Activation of adventitial DCs initiates and maintains T cell responses in the artery and breaks tissue tolerance in the perivascular space.

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