T-cell receptor repertoire of circulating gamma delta T-cells in Takayasu's arteritis

doi:10.1016/j.clim.2005.10.010

Clinical Immunology

Volume 118, Issues 2–3, February–March 2006, Pages 243-249

https://doi.org/10.1016/j.clim.2005.10.010 Get rights and content

Abstract

We studied T-cell receptor (TCR) repertoire of circulating gamma delta (γδ) T-cells in 20 patients with Takayasu's arteritis (TA), 20 healthy controls (HC), 7 follow up TA patients, and 10 patients with rheumatoid arthritis (RA) and 5 Wegener's granulomatosis (WG) patients as disease controls. Patients with TA (8.1 ± 5.1%) compared to HC (3.7 ± 2.1%, P = 0.014), RA (4.8 ± 0.6%, P = 0.032), and WG (4.2 ± 0.8%, P = 0.030) as well as active TA compared to inactive TA (13.9 ± 4.1% vs. 4.9 ± 1.5%; P < 0.001) had higher number of γδ T-cells. The numbers of Vδ1⁺ cells were significantly higher in patients with TA (40.0 ± 20.8%) than HC (13.1 ± 8.0%; P = 0.001), RA (19.5 ± 1.8%, P = 0.004), and WG (17.0 ± 3.9%, P = 0.007). The numbers of γδ T-cells normalized in all the 7 patients after 180 days of follow up (13.9 ± 4.1% vs. 6.9 ± 2.5%; P = 0.001). We also observed higher number of activated and IFN-γ producing γδ T-cells in active TA. Our data show that γδ T-cells particularly those bearing Vδ1 TCR may have an important role in the immunopathogenesis of TA.

Introduction

Takayasu's arteritis (TA) is a chronic inflammatory pan-arteritis characterized by stenosis and/or aneurysm of large elastic arteries, mainly the aorta and its major branches including pulmonary and coronary arteries. The disease shows high predilection for young females with peak incidence between 15 and 30 years of age. It is the most common vasculitis in India and the third most common vasculitis in the pediatric age group worldwide [1], [2], [3].

Etiopathogenesis of TA is not well understood, except that it is an autoimmune disease. The main pathologic findings of TA include predominance of T-cells in the vascular lesions, increased number of circulating activated T-cells bearing restricted T-cell receptor repertoire and increased proliferative response of these cells to aortal antigens [4], [5], [6]. These findings suggest a central role of T-cells in the pathogenesis of the disease. Most of the infiltrating T-cells in TA consist of gammadelta (γδ) T-cells that constitutes a distinctive pathological feature of this disease among other large vessel arteriopathies [7]. Heat shock protein (HSP)-65 and stress induced ligands like major histocompatibility complex (MHC) class I chain-related A (MICA), which constitutes major antigenic targets of γδ T-cells are highly expressed in the vascular lesions of TA [4], [8], [9]. Thus, it is possible that γδ T-cells from the circulation infiltrate the arterial wall in response to HSP-65, MICA or other related arterial antigen(s) and may be involved in the pathogenesis of the disease. However, knowledge on the role of these cells in the disease is very limited.

Therefore, in the present study, we decided to study the circulating γδ T-cells and their T-cell receptor (TCR) repertoire in patients with TA.

Section snippets

Subjects

After obtaining informed consents, 20 patients with TA (13 female, 7 male; mean age 29.1 ± 9.8 years), 20 age/sex-matched healthy controls (HC), 10 patients with rheumatoid arthritis (RA) (8 female, 2 male; mean age 33.6 ± 5.4 years), and 5 patients with Wegener's granulomatosis (WG) (all male; mean age 38.7 ± 7.5 years) as disease controls were enrolled in the study, which was approved by the Institutional Ethics Committee. All TA patients included in the study fulfilled at least three of the

Results

The representative flow cytometric dot-plots of γδ T-cells in patients with TA and controls are shown in Fig. 1. A significantly higher numbers of γδ T-cells were observed in patients with TA compared to HC, RA, and WG (8.1 ± 5.1% vs. 3.7 ± 2.1%, 4.8 ± 0.6% and 4.2 ± 0.8%; P = 0.014, 0.032 and 0.030, respectively) and in patients with active TA than inactive TA (13.9 ± 4.1% vs. 4.9 ± 1.5%; P = 0.001) (Fig. 2). The prevalence of γδ T-cells (numbers above cut-off value) was higher in patients

Discussion

In the present study, we have observed higher numbers of circulating γδ T-cells and a subset of Vδ1 TCR bearing cells in patients with TA. The numbers of γδ T-cells were higher in patients with active TA as compared to inactive TA but Vδ1 TCR bearing cells were increased in both the patient groups.

There is only one report on γδ T-cells receptor repertoire and that also in a single TA patient by Seko et al. [14]. These authors using RT-PCR have demonstrated mRNA of Vγ1, Vγ2, Vγ3, Vγ4, Vδ1, Vδ2,

Acknowledgments

This work was supported by the grant received from the Indian Council of Medical Research, New Delhi, India. We would also like to thank the Council of Scientific and Industrial Research, New Delhi, India, for providing Research Fellowship to the first author.

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Gamma-delta T cells have cytotoxic capabilities and can respond to stimuli via lymphokine production and proliferation [45]. Both the circulating number of gamma-delta T cells and their associated cytotoxicity levels have been normal or high in TAK patients compared with controls, where “controls” included people with GCA, granulomatosis with polyangiitis, rheumatoid arthritis (RA), SLE, and healthy individuals [45–48]. NK cells are important effector cells that do not require specific antigen recognition [49].
Giant cell arteritis (GCA) and Takayasu arteritis (TAK) are two types of primary large vessel vasculitis (LVV). LVV is an intractable, rare disease with a high relapse rate. Disease progression in asymptomatic patients is an important issue in the clinical management of LVV. Useful biomarkers associated with clinical phenotypes, disease activity, and prognosis may be present in peripheral blood. In this review, we focused on peripheral leukocyte counts, surface markers, functions, and gene expression in LVV patients. In particular, we explored longitudinal changes in circulating immune cell phenotypes during the active phase of the disease and during treatment. The numbers and phenotypes of leukocytes in the peripheral blood were different between LVV and healthy controls, GCA and TAK, LVV in active versus treatment phases, and LVV in treatment responders versus non-responders. Therefore, biomarkers obtained from peripheral blood immune cells may be useful for longitudinal monitoring of disease activity in LVV.
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La physiopathologie de l’artérite à cellules géantes (ACG) et de l’artérite de Takayasu (AT), deux vascularites granulomateuses affectant les vaisseaux de gros calibre, n’est que partiellement connue à ce jour en raison de l’absence de modèles expérimentaux et du nombre réduit de travaux fondamentaux ou de recherche translationnelle réalisés sur ce sujet. Cependant, des progrès dans la compréhension des mécanismes impliqués ont permis l’émergence de nouvelles approches thérapeutiques. L’ACG et l’AT surviennent sur un terrain génétique différent mais certains mécanismes immunopathologiques pourraient être communs. Le facteur déclenchant de ces vascularites n’est pas connu mais l’hypothèse, jamais confirmée à ce jour, d’un agent infectieux activant les cellules dendritiques de l’adventice est privilégiée. Cette activation de la réponse immunitaire innée permet le recrutement et l’activation des cellules de la réponse immunitaire cellulaire : lymphocytes T CD4 se polarisant en lymphocytes Th1 et Th17, lymphocytes T CD8 cytotoxiques et cellules natural killer. De plus, il existe un défaut en lymphocytes T régulateurs au cours de l’ACG et l’AT. La réponse immunitaire humorale pourrait jouer un rôle, notamment dans l’AT. Les cytokines produites par les cellules de l’immunité cellulaire (IL-17 et IFN-γ notamment) vont ensuite conduire au recrutement et à l’activation des monocytes qui vont se différencier en macrophages et en cellules géantes, lesquels vont produire des cytokines pro-inflammatoires (IL-1β et IL-6) responsables des signes généraux de l’ACG et l’AT et conduire au remodelage de la paroi vasculaire à l’origine des anévrysmes et des manifestations ischémiques de l’ACG et l’AT.
Giant cell arteritis (GCA) and Takayasu's arteritis (TA) are two granulomatous vasculitis affecting large arteries that present specific epidemiological and clinical features. Their pathogenesis is not fully understood but major advances have been obtained during the last years, thus allowing the emergence of new therapeutic strategies. GCA and TA develop on a specific genetic background but share some similarities regarding the immunological pathways involved in their pathogenesis. The trigger of these diseases is not clearly identified but it is thought that an infectious agent could activate and lead to the maturation of dendritic cells that are localized in the adventitia of arteries. Then, the cells of the adaptative immune response are recruited and activated: CD4 T cells that polarize into Th1 and Th17 cells, cytotoxic CD8 T cells and Natural Killer cells. Furthermore, the T regulatory cells (Treg) are decreased both in GCA and TA. Humoral immune response seems also to be involved, especially in TA. Then, the cytokines produced by T lymphocytes (especially IL-17 and IFN-γ) trigger the recruitment and activation of monocytes and their differentiation into macrophages and multinuclear giant cells that produce IL-1β and IL-6 that are responsible for general symptoms of GCA and TA, and cytotoxic mediators and growth factors that trigger the remodeling of the arterial wall leading to aneurysms and ischemic manifestations of GCA an TA.
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T-cell receptor repertoire of circulating gamma delta T-cells in Takayasu's arteritis

Abstract

Introduction

Section snippets

Subjects

Results

Discussion

Acknowledgments

Int. J. Cardiol.

Trans. R. Soc. Trop. Med. Hyg.

J. Lab. Clin. Med.

Takayasu's arteritis

J. Clin. Pathol.

Study of Takayasu's arteritis in children: clinical profile and management

J. Postgrad. Med.

Vasculitis from the pediatric perspective

Curr. Rheumatol. Rep.

Perforin secreting killer cell infiltration and expression of a 65-kD heat shock protein in aortic tissue of patients with Takayasu's arteritis

J. Clin. Invest.

A bias in the alpha T-cell receptor variable region gene usage in Takayasu's arteritis

Clin. Exp. Immunol.

Immunopathogenesis of Takayasu's arteritis

Heart Vessels

Large vessel vasculitides

Curr. Opin. Rheumatol.

Expression of costimulatory molecules (4-1BBL and Fas) and major histocompatibility class I chain-related A (MICA) in aortic tissue with Takayasu's arteritis

J. Vasc. Res.

Human γδ T cells respond to mycobacterial heat shock protein

Nature

American college of Rheumatology criteria for the classification of Takayasu arteritis

Arthritis Rheum.

Anti-annexin-V antibodies in Takayasu's arteritis: prevalence and relationship with disease activity

Clin. Exp. Immunol.