CD28−CD57+ T cells predominate in CD8 responses to glatiramer acetate

Ratts, Robert B.; Lovett-Racke, Amy E.; Choy, Judy; Northrop, Sara C.; Hussain, Rehana Z.; Karandikar, Nitin J.; Racke, Michael K.

doi:10.1016/j.jneuroim.2006.06.001

Cited by 14 publications

(8 citation statements)

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“…Initially thought to be pathogenic because of their preponderance in an oligoclonally expanded state in CNS lesions [31] and their ability to target oligodendrocytes in vitro [32, 33], a considerable body of evidence has established their protective role in the pathogenesis of MS. Several studies using the murine model of the disease have shown that CD8+ T cells are required for the amelioration of EAE [21, 22, 34–36]. In human studies, several reports have similarly demonstrated the regulatory properties of CD8+ T cells in MS [20, 37–42]. Additionally, a recent report further suggested that the preponderance of CD8+ T cells in MS lesions might be explained by the concomitant upregulation of HLA-E in the white lesions of multiple sclerosis patients [43].…”

Section: Discussionmentioning

confidence: 99%

“…For instance, it is tempting to speculate that one could predict a potential relapse by tracking the levels of the terminally differentiated CD8+ T cells, perhaps helping with pre-emptive treatment. It is also interesting to note that the same terminally differentiated population is predominantly expanded and activated by Copaxone treatment [37]. Based on the observation that CD8+ T cells from patients with MS can still be potentiated, adoptive transfer of in vitro potentiated CD8+ Tregs could also be considered as a viable therapeutic modality for MS patients.…”

Section: Discussionmentioning

confidence: 99%

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Disease exacerbation of multiple sclerosis is characterized by loss of terminally differentiated autoregulatory CD8+ T cells

Cunnusamy

Baughman

Franco

et al. 2014

Clinical Immunology

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Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). Although its etiology remains unknown, pathogenic T cells are thought to underlie MS immune pathology. We recently showed that MS patients harbor CNS-specific CD8+ Tregs that are deficient during disease relapse. We now demonstrate that CNS-specific CD8+ Tregs were cytolytic and could eliminate pathogenic CD4+ T cells. These CD8+ Tregs were present primarily in terminally differentiated (CD27−, CD45RO−) subset and their suppression was IFNγ, perforin and granzyme B-dependent. Interestingly, MS patients with acute relapse displayed a significant loss in terminally differentiated CD8+ T cells, with a concurrent loss in expression of perforin and granzyme B. Pre-treatment of exacerbation-derived CD8+ T cells with IL-12 significantly restored suppressive capability of these cells through upregulation of granzyme B. Our studies uncover immune-suppressive mechanisms of CNS-specific CD8+ Tregs, and may contribute to design of novel immune therapies for MS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Disease exacerbation of multiple sclerosis is characterized by loss of terminally differentiated autoregulatory CD8+ T cells

Cunnusamy

Baughman

Franco

et al. 2014

Clinical Immunology

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“…We have demonstrated an unexpected and novel immune regulatory role for both CNS-specific autoreactive CD8+ T cells as well as therapeutically induced CD8+ T cell responses in the context of MS and its animal model, EAE [6, 9–13, 17–24]. The mechanisms, biology and potential therapeutic benefit of these CD8+ T cells is a major focus of studies in our laboratory and the predominant focus of this review.…”

Section: Introductionmentioning

confidence: 99%

Immune regulation of multiple sclerosis by CD8+ T cells

2014

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The role of CD8+ T cells in the process of autoimmune pathology has been both understudied and controversial. Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS) with an underlying T-cell-mediated immunopathology. CD8+ T cells are the predominant T cells in human MS lesions, showing oligoclonal expansion at the site of pathology. It is still unclear whether these cells represent pathogenic immune responses or disease-regulating elements. Through studies in human MS and its animal model, experimental autoimmune encephalomyelitis (EAE), we have discovered two novel CD8+ T cell populations that play an essential immunoregulatory role in disease: (1) MHC class Ia-restricted neuroantigen-specific “autoregulatory” CD8+ T cells and (2) glatiramer acetate (GA/Copaxone®) therapy-induced Qa-1/HLA-E-restricted GA-specific CD8+ T cells. These CD8 Tregs suppress proliferation of pathogenic CD4+CD25- T-cells when stimulated by their cognate antigens. Similarly, CD8+ Tregs significantly suppress EAE when transferred either pre-disease induction or during peak disease. The mechanism of disease inhibition depends, at least in part, on an antigen-specific, contact-dependent process and works through modulation of CD4+ T cell responses as well as antigen presenting cells (APC) through a combination of cytotoxicity and cytokine-mediated modulation. This review provides an overview of our understanding of CD8+ T cells in immune-mediated disease, focusing particularly on our findings about regulatory CD8+ T cells both in MS and EAE. Clinical relevance of these novel CD8-regulatory populations is discussed, providing insights into a potentially intriguing, novel therapeutic strategy for these diseases.

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“…We thus used a combination of CD28 and CD57, along with either CD8 or CD4, to test whether these markers would enhance immunologic discrimination between MS and healthy subjects. Our recent data demonstrates that the evaluation of these 2 markers on CD8+ T cell responses can robustly discriminate responses of MS patients from those of healthy subjects [59,60]. …”

Section: Introductionmentioning

confidence: 99%

Multiparameter Flow Cytometric Assays to Quantify Effector and Regulatory T-Cell Function in Multiple Sclerosis

et al. 2014

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The immune system plays a major pathological and regulatory role in multiple sclerosis (MS) and, therefore, is a focus of extensive research. Animal models of MS have been crucial in understanding the pathological processes in MS and developing certain treatments, however, all crucial aspects of the human disease may not be appropriately modeled. With the exception of detecting oligoclonal bands and IgG synthesis in cerebrospinal fluids of MS patients, there has not been major progress in the development of immunologic tests that can be used for diagnosis of MS. Further, due to the lack of validated immune assays, routine monitoring of the immune system following therapy initiation is not a part of standard patient care in MS. This is critical since immunomodulatory therapies used for MS treatment are not benign and, more importantly, there is a considerable variation in clinical responses in MS patients initiating such therapies. Flow cytometry is a powerful tool that can be used for studying both the phenotype and function of immune cells. The studies described here will demonstrate how flow cytometry can be used to apply current knowledge about the MS immune system to develop a diagnostic laboratory test for the immunologic monitoring of this disease. Importantly, we will also show that the multiparameter flow cytometry based assay developed by us can also be implemented for the immunologic evaluation of therapeutic success in MS patients.

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CD28−CD57+ T cells predominate in CD8 responses to glatiramer acetate

Cited by 14 publications

References 50 publications

Disease exacerbation of multiple sclerosis is characterized by loss of terminally differentiated autoregulatory CD8+ T cells

Disease exacerbation of multiple sclerosis is characterized by loss of terminally differentiated autoregulatory CD8+ T cells

Immune regulation of multiple sclerosis by CD8+ T cells

Multiparameter Flow Cytometric Assays to Quantify Effector and Regulatory T-Cell Function in Multiple Sclerosis

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