Elsevier

Clinical Immunology

Volume 133, Issue 3, December 2009, Pages 364-374
Clinical Immunology

Differential susceptibility to apoptosis of CD4+T cells expressing CCR5 and CXCR3 in patients with MS

https://doi.org/10.1016/j.clim.2009.08.012Get rights and content

Abstract

We aimed to evaluate differences in the susceptibility to apoptosis of CD4+CCR5+ and CD4+CXCR3+T cells between MS patients (N = 41) and controls (N = 15) 6 days after activation of peripheral blood cells with anti-CD3 antibodies and 24 h following stimulation with anti-Fas antibodies. Susceptibility to anti-CD3 induced activation-induced cell death (AICD) and Fas-mediated apoptosis was selectively increased in CD4+CCR5+T cells compared with CD4+CCR5− and CD4+CXCR3−/+T cells. Compared with controls, CD4+CCR5+T cells from patients with primary progressive MS (PPMS) were more resistant to anti-CD3-induced AICD and anti-Fas-induced apoptosis determined with the mitochondrial probe DiOC6 (3-3′-dihexyloxacarboyanine iodide). Our findings point to a differential regulation in the susceptibility to apoptosis of CD4+T cells expressing CCR5 and CXCR3 and suggest an impairment in the mitochondria-mediated apoptotic deletion of CD4+CCR5+T cells in PPMS patients that may lead to their chronic persistence in peripheral blood from these patients.

Introduction

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by perivascular T cell and macrophage infiltrates leading to demyelination. The pathogenesis of MS is thought to involve self antigen-reactive T lymphocytes that have the capacity to invade the CNS and promote tissue damage [1]. Programmed cell death (apoptosis) is an important anti-autoimmune mechanism that deletes potentially pathogenic autoreactive lymphocytes from the circulation and tissues, and limits tissue damage caused by immune responses [2]. Evidence exists that apoptotic deletion of autoreactive lymphocytes is defective in patients with MS, thereby permitting these cells to perpetuate a continuous cycle of inflammation within the CNS [3]. For instance, death receptor Fas (CD95) defects have been reported in T lymphocytes from MS patients, with a consequent decrease in their susceptibility to cell death [4], [5], [6]. In addition, studies in MS have revealed impairments in the apoptotic deletion of mitogen-stimulated and myelin basic protein (MBP)-reactive or peptide-specific T lymphocytes [7]. Furthermore, both activated T cells and T cell lines derived from MS patients showed less spontaneous apoptosis and were less sensitive or even resistant to induced apoptosis [4], [5], [7], [8], All these findings are indicative of a defective functioning of Fas or its downstream mechanisms in MS [9]. As a result, the reduced susceptibility to apoptosis in T cells from MS patients may prolong the survival of circulating autoreactive T cells and limit their elimination in the CNS.

Chemokine receptors are among the molecules that mediate recruitment of specific leukocyte populations into the inflamed tissues [10]. After activation, CD4+T cells acquire new chemokine receptors, and Th1 and Th2 cells express distinct patterns of chemokine receptors. CCR5 and CXCR3 are two chemokine receptors associated with trafficking of activated memory T cells, predominantly of a Th1 phenotype, to sites of inflammation in vivo [11]. Several reports have implicated CCR5 and CXCR3 in the pathogenesis of MS [12], [13], [14], [15], [16], [17].

In a recent and descriptive study, we found that the number of activated CD4+T cells expressing the chemokine receptor CCR5 was elevated in peripheral blood of MS patients, and these CD4+CCR5+T cells expressed significantly less Fas death receptor compared with healthy controls [13]. Based on these observations, we sought to evaluate functional differences in the susceptibility to apoptosis of CD4+CCR5+and CD4+CXCR3+T cells between MS patients with different clinical forms and healthy controls.

Section snippets

Patients

Forty-one patients with clinically definite MS and 15 healthy controls were included in the study. Patients were labeled as primary-progressive MS (PPMS, N = 17), or relapsing–remitting MS (RRMS, N = 24) (12 patients untreated and 12 treated with interferon-beta (IFNβ)) according to the Lublin and Reingold classification [18].

None of the patients had received immunomodulatory therapy in the 12 months prior to blood collection. No relapses were recorded nor had the patients received corticosteroids

Anti-CD3-induced AICD is selectively increased in CD4+CCR5+T cells compared with CD4+CXCR3+T cells

We first investigated differences in susceptibility to apoptosis between T cell populations positive and negative for chemokine receptors in MS patients and controls. The percentage of apoptotic cells was measured after 6 days of incubation with anti-CD3 in the presence of recombinant IL-2. When data from MS patients and controls were pooled together, the percentage of apoptotic cells was significantly increased in CD4+CCR5+T cells compared with CD4+CCR5−T cells following staining with annexin

Discussion

Apoptosis or programmed cell death is an essential physiological process that plays an important function in homeostasis and may be involved in the prevention of autoimmune diseases such as MS [2]. The pathogenesis of MS is unknown, but evidence exists for a role of T cells expressing the chemokine receptors CCR5 and CXCR3 in the trafficking of activated memory T cells, of Th1 phenotype, into the CNS of MS patients [12], [16]. We found that despite similar functions in the recruitment of cells

Acknowledgments

The study was supported by a grant from the “Fondo de Investigación Sanitaria” (FIS-02/0160), Ministry of Science and Innovation, Spain. The authors thank the “Red Española de Esclerosis Múltiple (REEM)” sponsored by the FIS, and the “Ajuts per donar Suport als Grups de Recerca de Catalunya (SGR 2005-1081)” sponsored by the “Agència de Gestió d'Ajuts Universitaris i de Recerca” (AGAUR), Generalitat de Catalunya, Spain.

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