Natural killer cell phenotype and clinical response to interferon-beta therapy in multiple sclerosis

Martínez-Rodríguez, José Enrique; López‐Botet, Miguel; Munteis, Elvira; Río, Jordi; Roquer, Jaume; Montalbán, Xavier; Comabella, Manuel

doi:10.1016/j.clim.2011.09.006

Cited by 63 publications

(56 citation statements)

References 31 publications

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“…NKG2A + CD8 T cells carrying regulatory functions were also shown in the MS animal model, experimental autoimmune encephalomyelitis (34). In contrast, Martinez-Rodriguez et al (32) reported a similar proportion of CD8 T cells carrying NKG2A for controls and untreated MS patients and of NK cells expressing NKG2A and/or NKG2C. Similarly, we rarely found NKG2A + T cells when we performed ex vivo analysis of blood cells and could not detect any differences between MS patients and controls (Fig.…”

Section: Discussionsupporting

confidence: 44%

“…However, such increased percentage of lymphocytes expressing NKG2C is observed predominantly in CD8 T cells or NK cells compared with healthy controls (7,11). The proportion of CD8 T cells expressing NKG2C was reported to be slightly increased in untreated MS patients (3.0%) compared with controls (2.0%) (32). However, we observed a comparable low level of CD8 T cells expressing NKG2C in both groups (3.6% in MS patients compared with 3.4% in controls).…”

Section: Discussionmentioning

confidence: 96%

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Cytotoxic NKG2C+ CD4 T Cells Target Oligodendrocytes in Multiple Sclerosis

Zaguia

Saikali

Ludwin

et al. 2013

The Journal of Immunology

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The mechanisms whereby immune cells infiltrating the CNS in multiple sclerosis patients contribute to tissue injury remain to be defined. CD4 T cells are key players of this inflammatory response. Myelin-specific CD4 T cells expressing CD56, a surrogate marker of NK cells, were shown to be cytotoxic to human oligodendrocytes. Our aim was to identify NK-associated molecules expressed by human CD4 T cells that confer this oligodendrocyte-directed cytotoxicity. We observed that myelin-reactive CD4 T cell lines, as well as short-term PHA-activated CD4 T cells, can express NKG2C, the activating receptor interacting with HLA-E, a nonclassical MHC class I molecule. These cells coexpress CD56 and NKG2D, have elevated levels of cytotoxic molecules FasL, granzyme B, and perforin compared with their NKG2C-negative counterparts, and mediate significant in vitro cytotoxicity toward human oligodendrocytes, which upregulated HLA-E upon inflammatory cytokine treatment. A significantly elevated proportion of ex vivo peripheral blood CD4 T cells, but not CD8 T cells or NK cells, from multiple sclerosis patients express NKG2C compared with controls. In addition, immunohistochemical analyses showed that multiple sclerosis brain tissues display HLA-E+ oligodendrocytes and NKG2C+ CD4 T cells. Our results implicate a novel mechanism through which infiltrating CD4 T cells contribute to tissue injury in multiple sclerosis.

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Section: Discussionsupporting

confidence: 44%

Section: Discussionmentioning

confidence: 96%

Cytotoxic NKG2C+ CD4 T Cells Target Oligodendrocytes in Multiple Sclerosis

Zaguia

Saikali

Ludwin

et al. 2013

The Journal of Immunology

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“…However, following several MS therapies (e.g., daclizumab and IFN-b), an expansion of regulatory CD56 bright NK cells is observed, which is associated with a good response to treatment (47,48). Therapy with IFN-b induces a decrease in the cytotoxicity and number of CD56 dim cells in the periphery, whereas in the case of natalizumab, CD56 bright expansion is speculated to have its origin in recruitment from lymphoid organs (3,49).…”

Section: Cd56mentioning

confidence: 99%

Human CD56bright NK Cells: An Update

Michel

Poli

Cuapio

et al. 2016

The Journal of Immunology

305

273

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Human NK cells can be subdivided into various subsets based on the relative expression of CD16 and CD56. In particular, CD56brightCD16−/dim NK cells are the focus of interest. They are considered efficient cytokine producers endowed with immunoregulatory properties, but they can also become cytotoxic upon appropriate activation. These cells were shown to play a role in different disease states, such as cancer, autoimmunity, neuroinflammation, and infection. Although their phenotype and functional properties are well known and have been extensively studied, their lineage relationship with other NK cell subsets is not fully defined, nor is their precise hematopoietic origin. In this article, we summarize recent studies about CD56bright NK cells in health and disease and briefly discuss the current controversies surrounding them.

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“…Of interest, the change in NK differentiation state and NK receptor expression in response to IFNβ has also been associated with clinical response [57]. In contrast to EOMES, mean TBX21 expression was increased to healthy control levels on IFNβ, but with a high level of variability, suggestive of significant inter-individual response to therapy, which may make it particularly useful for personalising therapy.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

The low EOMES/TBX21 molecular phenotype in multiple sclerosis reflects CD56+ cell dysregulation and is affected by immunomodulatory therapies

McKay

Gatt

Fewings

et al. 2016

Clinical Immunology

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Multiple Sclerosis (MS) is an autoimmune disease treated by therapies targeting peripheral blood cells. We previously identified that expression of two MS-risk genes, the transcription factors EOMES and TBX21 (ET), was low in blood from MS and stable over time. Here we replicated the low ET expression in a new MS cohort (p<0.0007 for EOMES, p < 0.028 for TBX21) and demonstrate longitudinal stability (p<10 -4 ) and high heritability (h 2 =0.48 for EOMES) for this molecular phenotype. Genes whose expression correlated with ET, especially those controlling cell migration, further defined the phenotype. CD56+ cells and other subsets expressed lower levels of Eomes or T-bet protein and/or were underrepresented in MS. EOMES and TBX21 risk SNP genotypes, and serum EBNA-1 titres were not correlated with ET expression, but HLA-DRB1*1501 genotype was. ET expression was normalised to healthy control levels with natalizumab, and was highly variable for glatiramer acetate, fingolimod, interferon-beta, dimethyl fumarate.

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Natural killer cell phenotype and clinical response to interferon-beta therapy in multiple sclerosis

Cited by 63 publications

References 31 publications

Cytotoxic NKG2C+ CD4 T Cells Target Oligodendrocytes in Multiple Sclerosis

Cytotoxic NKG2C+ CD4 T Cells Target Oligodendrocytes in Multiple Sclerosis

Human CD56bright NK Cells: An Update

The low EOMES/TBX21 molecular phenotype in multiple sclerosis reflects CD56+ cell dysregulation and is affected by immunomodulatory therapies

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