Gate D, Saligrama N, Leventhal O, Yang AC, Unger MS, Middeldorp J, Chen K, Lehallier B, Channappa D, De Los Santos MB, McBride A, Pluvinage J, Elahi F, Tam GK, Kim Y, Greicius M, Wagner AD, Aigner L, Galasko DR, Davis MM, Wyss-Coray T. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease. Nature. 2020 Jan;577(7790):399-404. Epub 2020 Jan 8 PubMed.

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  1. We and others have been exploring the role of T cells in cognition and in neurodegenerative diseases and aging and this beautiful study shows, for the first time, a close association among T cells, cognition, and AD in humans. These elegant findings on expansion of Epstein-Barr virus-reactive CD8 T cells in the CSF of AD patients are extremely interesting and intriguing. A role of viral infection as a driving factor in pathogenesis of AD has been proposed by Rudy Tanzi and late Rob Moir (who has just passed away a couple of weeks ago). Their ideas were first met with skepticism and now the current work points in the same direction.

    On a personal note, this work is exciting because it shows a human relevance of neuroimmune interactions that we have been studying in mice. Future works will be aimed at better understanding how and why these antiviral T cells are accumulating in the CSF, the function or dysfunction of meningeal lymphatics in drainage of these T cells into the periphery, and the mechanisms underlying their impact on cognition. 

     

    View all comments by Jonathan Kipnis

  2. This article by Gate et al. elegantly shows the presence of clonally expanded CD8 T cells in Alzheimer’s disease. The primary question regarding the finding is the degree to which these cells are secondary to the disease process or actually play a pathogenic or disease-amplifying role in AD. Though they aren’t found in healthy, age-matched individuals, they do not appear to be 100 percent specific to AD, because they are also seen to some extent in Parkinson’s disease. Their cross-reactivity with certain Epstein-Barr virus peptides is intriguing but in no way establishes a link between EBV and AD, as the authors also caution. Their apparent linkage to cognition could simply represent their secondary dependence on CNS damage in AD.

    Antigen-specific T cell responses to Aβ peptides and α-synuclein have been shown in AD and PD, respectively, and it is not yet clear how these pro-inflammatory type CD8+ cells relate to T cell antigen-specific responses to pathogenic proteins that accumulate in these diseases. Demonstrating that these expanded clonal T cells change with treatment in people (which is not a simple task) or identifying them in animal models of AD and showing a true pathogenic role early in mouse disease development by manipulating them specifically, will now be important approaches to establish their relevance.

    View all comments by Dennis Selkoe

  3. Overall I think this is a beautiful study.

    It makes a clear point that immune components are essential for our understanding of Alzheimer’s disease. Whether these are causal factors or part of the repair mechanism, or a repair system that went wrong, it suggests that we can use the immune system as an early detection tool for malfunctions of the brain and potentially as a treatment vehicle. The detection of clones for non-self antigens, although stated with caution, suggests that pathogenic factors may be part of the pathology. Overall, I think that CD8 cells still receive limited attention in our perception of the immune compartment in the brain, and I am sure that this study will shift the focus.

    View all comments by Asya Rolls

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