In JoVE (1)

Other Publications (10)

Articles by Andreas Schulte-Mecklenbeck in JoVE

Other articles by Andreas Schulte-Mecklenbeck on PubMed

The Two-pore Domain K2 P Channel TASK2 Drives Human NK-cell Proliferation and Cytolytic Function

European Journal of Immunology. Sep, 2015  |  Pubmed ID: 26140335

Natural killer (NK) cells are a subset of cytotoxic lymphocytes that recognize and kill tumor- and virus-infected cells without prior stimulation. Killing of target cells is a multistep process including adhesion to target cells, formation of an immunological synapse, and polarization and release of cytolytic granules. The role of distinct potassium channels in this orchestrated process is still poorly understood. The current study reveals that in addition to the voltage-gated KV 1.3 and the calcium-activated KCa 3.1 channels, human NK cells also express the two-pore domain K2 P channel TASK2 (TWIK-related acid-sensitive potassium channel). Expression of Task2 varies among NK-cell subsets and depends on their differentiation and activation state. Despite its different expression in TASK2(high) CD56(bright) CD16(-) and TASK2(low) CD56(dim) CD16(+) NK cells, TASK2 is involved in cytokine-induced proliferation and cytolytic function of both subsets. TASK2 is crucial for leukocyte functional antigen (LFA-1) mediated adhesion of both resting and cytokine-activated NK cells to target cells, an early step in killing of target cells. With regard to the following mechanism, TASK2 plays a role in release of cytotoxic granules by resting, but not IL-15-induced NK cells. Taken together, our data exhibit two-pore potassium channels as important players in NK-cell activation and effector function.

Neurocognitive Decline in HIV Patients is Associated with Ongoing T-cell Activation in the Cerebrospinal Fluid

Annals of Clinical and Translational Neurology. Sep, 2015  |  Pubmed ID: 26401512

HIV-associated neurocognitive disorders (HAND) remain a challenge despite combination antiretroviral therapy (cART). Immune cell activation has been implicated to play a major role in the development of HAND.

Dimethyl Fumarate Treatment Alters Circulating T Helper Cell Subsets in Multiple Sclerosis

Neurology(R) Neuroimmunology & Neuroinflammation. Feb, 2016  |  Pubmed ID: 26767188

To evaluate the effect of dimethyl fumarate (DMF; Tecfidera, Biogen, Weston, MA) on CD4(+) and CD8(+) T cell subsets in patients with multiple sclerosis (MS).

Impaired NK-mediated Regulation of T-cell Activity in Multiple Sclerosis is Reconstituted by IL-2 Receptor Modulation

Proceedings of the National Academy of Sciences of the United States of America. May, 2016  |  Pubmed ID: 27162345

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) resulting from a breakdown in peripheral immune tolerance. Although a beneficial role of natural killer (NK)-cell immune-regulatory function has been proposed, it still needs to be elucidated whether NK cells are functionally impaired as part of the disease. We observed NK cells in active MS lesions in close proximity to T cells. In accordance with a higher migratory capacity across the blood-brain barrier, CD56(bright) NK cells represent the major intrathecal NK-cell subset in both MS patients and healthy individuals. Investigating the peripheral blood and cerebrospinal fluid of MS patients treated with natalizumab revealed that transmigration of this subset depends on the α4β1 integrin very late antigen (VLA)-4. Although no MS-related changes in the migratory capacity of NK cells were observed, NK cells derived from patients with MS exhibit a reduced cytolytic activity in response to antigen-activated CD4(+) T cells. Defective NK-mediated immune regulation in MS is mainly attributable to a CD4(+) T-cell evasion caused by an impaired DNAX accessory molecule (DNAM)-1/CD155 interaction. Both the expression of the activating NK-cell receptor DNAM-1, a genetic alteration consistently found in MS-association studies, and up-regulation of the receptor's ligand CD155 on CD4(+) T cells are reduced in MS. Therapeutic immune modulation of IL-2 receptor restores impaired immune regulation in MS by increasing the proportion of CD155-expressing CD4(+) T cells and the cytolytic activity of NK cells.

Distinct Pattern of Lesion Distribution in Multiple Sclerosis is Associated with Different Circulating T-helper and Helper-like Innate Lymphoid Cell Subsets

Multiple Sclerosis (Houndmills, Basingstoke, England). Aug, 2016  |  Pubmed ID: 27481205

Distinct lesion topography in relapsing-remitting multiple sclerosis (RRMS) might be due to different antigen presentation and/or trafficking routes of immune cells into the central nervous system (CNS).

B7-H1 Shapes T-cell-mediated Brain Endothelial Cell Dysfunction and Regional Encephalitogenicity in Spontaneous CNS Autoimmunity

Proceedings of the National Academy of Sciences of the United States of America. Oct, 2016  |  Pubmed ID: 27671636

Molecular mechanisms that determine lesion localization or phenotype variation in multiple sclerosis are mostly unidentified. Although transmigration of activated encephalitogenic T cells across the blood-brain barrier (BBB) is a crucial step in the disease pathogenesis of CNS autoimmunity, the consequences on brain endothelial barrier integrity upon interaction with such T cells and subsequent lesion formation and distribution are largely unknown. We made use of a transgenic spontaneous mouse model of CNS autoimmunity characterized by inflammatory demyelinating lesions confined to optic nerves and spinal cord (OSE mice). Genetic ablation of a single immune-regulatory molecule in this model [i.e., B7-homolog 1 (B7-H1, PD-L1)] not only significantly increased incidence of spontaneous CNS autoimmunity and aggravated disease course, especially in the later stages of disease, but also importantly resulted in encephalitogenic T-cell infiltration and lesion formation in normally unaffected brain regions, such as the cerebrum and cerebellum. Interestingly, B7-H1 ablation on myelin oligodendrocyte glycoprotein-specific CD4(+) T cells, but not on antigen-presenting cells, amplified T-cell effector functions, such as IFN-γ and granzyme B production. Therefore, these T cells were rendered more capable of eliciting cell contact-dependent brain endothelial cell dysfunction and increased barrier permeability in an in vitro model of the BBB. Our findings suggest that a single immune-regulatory molecule on T cells can be ultimately responsible for localized BBB breakdown, and thus substantial changes in lesion topography in the context of CNS autoimmunity.

Alemtuzumab Treatment Alters Circulating Innate Immune Cells in Multiple Sclerosis

Neurology(R) Neuroimmunology & Neuroinflammation. Dec, 2016  |  Pubmed ID: 27766281

To characterize changes in myeloid and lymphoid innate immune cells in patients with relapsing-remitting multiple sclerosis (MS) during a 6-month follow-up after alemtuzumab treatment.

Regulatory Functions of Natural Killer Cells in Multiple Sclerosis

Frontiers in Immunology. 2016  |  Pubmed ID: 28066417

There is increasing evidence that natural killer (NK) cells exhibit regulatory features. Among them, CD56(bright) NK cells have been suggested to play a major role in controlling T cell responses and maintaining homeostasis. Dysfunction in NK cell-mediated regulatory features has been recently described in untreated multiple sclerosis (MS), suggesting a contribution to MS pathogenesis. Moreover, biological disease-modifying treatments effective in MS apparently enhance the frequencies and/or regulatory function of NK cells, further pointing toward an immunoprotective role of NK cells in MS. Here, we summarize the current knowledge on the regulatory functions of NK cells, based on their interactions with other cells belonging to the innate compartment, as well as with adaptive effector cells. We review the more recent data reporting disruption of NK cell/T cell interactions in MS and discuss how disease-modifying treatments for MS affect NK cells.

Neurochondrin is a Neuronal Target Antigen in Autoimmune Cerebellar Degeneration

Neurology(R) Neuroimmunology & Neuroinflammation. Jan, 2017  |  Pubmed ID: 27957508

To report on a novel neuronal target antigen in 3 patients with autoimmune cerebellar degeneration.

Reply to Liu Et Al.: Haplotype Matters: CD226 Polymorphism As a Potential Trigger for Impaired Immune Regulation in Multiple Sclerosis

Proceedings of the National Academy of Sciences of the United States of America. Feb, 2017  |  Pubmed ID: 28137888

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