Differential susceptibility to apoptosis of CD4+T cells expressing CCR5 and CXCR3 in patients with MS
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.
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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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2019, Journal of AutoimmunityCitation Excerpt :Both extrinsic and intrinsic apoptotic pathways converge to the cleavage of pro-caspase-3 into its mature active form [71]. A number of studies investigating this process in MS blood cells showed lower susceptibility of PBMC from RRMS and secondary progressive MS patients to cell death [72] and defective caspase-3 activation and apoptosis in T lymphocytes of RRMS [73] and primary progressive MS [74] patients. In contrast, our study identified higher caspase-3 expression and activation as well as increased Annexin-V levels in B cells and monocytes of MS patients as compared to the healthy counterparts.
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2015, Journal of NeuroimmunologyCitation Excerpt :Taken together, these data suggest that the apoptotic machinery is functionally, but not intrinsically or genetically, impaired at peripheral level in MS. In addition, peripheral T lymphocyte activation is considered a hallmark of MS and expression of CCR5 and CXCR3 has been shown to characterize T cell subpopulations in MS with different functions. In fact, CD4 + CCR5 + T cells in PPMS were shown to be more resistant to anti-CD3 activation-induced cell death (AICD) and Fas-induced cell death and exhibited lower susceptibility to mitochondrial cell death (Julia et al., 2009). Furthermore, the impairment of AICD in RRMS might be also due to a failure of caspase-3 activation (Moreno et al., 2014).
Activation-induced cell death in T lymphocytes from multiple sclerosis patients
2014, Journal of NeuroimmunologyCitation Excerpt :We investigated spontaneous apoptosis and AICD in T cells from different clinical forms and activity phases of the disease. The results of our work are in agreement with previous reports indicating an impaired induction of apoptosis in peripheral T lymphocytes from MS patients (Sharief, 2000; Petcu et al., 2006; Julia et al., 2009). In addition to this observation, we found that AICD was mainly altered in patients with RRMS in clinical remission and it was not affected in patients with PPMS or RRMS patients during relapses, pointing to different pathogenic mechanisms underlying the different clinical forms of MS.
The role of T cell apoptosis in nervous system autoimmunity
2012, Autoimmunity ReviewsCitation Excerpt :Another aspect is the different susceptibility to apoptosis of CD4+ T cells expressing the chemokine receptors CCR5 and CXCR3, which play a role in trafficking of activated memory T cells, predominantly of a TH1 phenotype, to sites of inflammation in vivo and have been implicated in the pathogenesis of MS by several reports [75–77]. CD4+CCR5+ T cells display a peculiarly high susceptibility to Fas-mediated apoptosis, but those from PPMS patients appear to be less sensitive than those from controls [78]. Moreover, TNF-α, IL-4, IL-10, TGF-β, CCR5, CXCR3, Fas and FasL mRNA levels have been correlated with the course of disability over a 10 year period.
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