Wednesday, 13 January 2016

Natual Killer cells dictate recovery?

Liu Q, Sanai N, Jin WN, La Cava A, Van Kaer L, Shi FD. Neural stem cells sustain natural killer cells that dictate recovery from brain inflammation. Nat Neurosci. 2016 Jan 11. doi: 10.1038/nn.4211. [Epub ahead of print]

Recovery from organ-specific autoimmune diseases largely relies on the mobilization of endogenous repair mechanisms and local factors that control them. Natural killer (NK) cells are swiftly mobilized to organs targeted by autoimmunity and typically undergo numerical contraction when inflammation wanes. We report the unexpected finding that NK cells are retained in the brain subventricular zone (SVZ) during the chronic phase ofmultiple sclerosis in humans and its animal model in mice. These NK cells were found preferentially in close proximity to SVZ neural stem cells (NSCs) that produce interleukin-15 and sustain functionally competent NK cells. Moreover, NK cells limited the reparative capacity of NSCs following brain inflammation. These findings reveal that reciprocal interactions between NSCs and NK cells regulate neurorepair.




The subventricular zone (SVZ) is a paired brain structure situated throughout the lateral walls of the lateral ventricles. It is composed of four distinct layers of variable thickness and cell density, as well as cellular composition.



Along with the dentate gyrus of the hippocampus, the SVZ is one of two places where neurogenesis (nerve growth) has been found to occur in the adult mammalian brain.

In MS it is reported that Cells expressing the NK cell marker NKp46 densely populated brain sections from patients in the chronic stage of MS and were predominantly located in the SVZ.

In EAE they find that these type of cells accumulate in the subventricular zone after the attack, when cells in the spinal cord are dropping. It is suggested that the neural stem cells may secrete factors that promote the natural killer cells. These astrocyte like (Type B) neural stem cells produce interleukin 15 to sustain the natural killer cells that produce gamma interferon. If they block interleukin 15 the NK cells were not retained. Interestingly if they killed the natural killers cells with and antibody then there was more subentricular zone stem cell activity and it turns out the NK cells were killing the subventricular zone cells. They deplete NK 1.1 cells after recoery and it promotes more recovery. They found found that NK cells remained tolerant to SVZ NSCs during the peak phase of EAE, with increased expression of Qa1. In contrast, tolerance to NSCs was ablated during the late stages (30–60 dpi) owing to downregulation of Qa1. Therefore, the differential role played by NK cells during different phases of EAE may critically depend on dynamic alterations in their tolerance to NSCs and may involve Qa1, a ligand of the inhibitory NK cell receptor NKG2A.

Natural killer cells or NK cells are a type of cytotoxic lymphocyte critical to the innate immune system. The role NK cells play is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to viral-infected cells, acting at around 3 days after infection, and respond to tumor formation. Typically, immune cells detect major histocompatibility complex (MHC) presented on infected cell surfaces, triggering cytokine release, causing lysis or apoptosis. NK cells are unique, however, as they have the ability to recognize stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the initial notion that they do not require activation to kill cells that are missing "self" markers of MHC class 1. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

NK cells differ from natural killer T cells (NKTs) phenotypically, by origin and by respective effector functions; often, NKT cell activity promotes NK cell activity by secreting IFNγ. In contrast to NKT cells, NK cells do not express T-cell antigen receptors (TCR) or pan T marker CD3 or surface immunoglobulins (Ig) B cell receptors, but they usually express the surface markers CD16 (FcγRIII) and CD56 in humans, NK1.1 or NK1.2 in C57BL/6 mice. The NKp46 cell surface marker constitutes, at the moment, another NK cell marker of preference being expressed in both humans, several strains of mice .

So this studies implies that depletion of NK cells is good for recovery, but point 19 of the ARRIVE guidelines asks what is the the translatable relevance of study. 

Is it arrogant of me(as I stand accused) to ask how does this relate to the action of daclizumab? This expands a population of Natural killer cells that express CD56 and inhibits relapsing MS does it stop their recovery? This was not mentioned or addressed in the paper.....so good reviewing again :-). 

I suspect there will be many people rushing to there histology sections to see if the NK cells are there...wouldn't it be interesting to look at a relapsing disease?

3 comments:

  1. Very interesting, more good questions.

    ReplyDelete
  2. "Is it arrogant of me(as I stand accused) to ask how does this relate to the action of daclizumab? " -
    I don't know, but this is the first question which came to my mind - I must be equally arrogant

    ReplyDelete

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