. Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer's disease pathology. Nat Commun. 2015 Aug 18;6:7967. PubMed.


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  1. This work by Baruch et al. sheds further light on the role of circulating immune cells in the pathogenesis of Alzheimer's disease (AD). The authors found that systemic Foxp3+ regulatory T cells (Tregs) represent a negative player in 5XFAD mice presenting early Aβ pathology by modulating the recruitment of leukocytes to the CNS through the choroid plexus. These results suggest the potential of modulating systemic Treg function as a novel strategy for AD immunotherapy.

    A remarkable finding of this study is that one-week treatment inhibiting systemic Tregs led to significant reduction of Aβ accumulation in 5XAD mice during later stages of disease (10 months), which are normally characterized by robust cerebral Aβ plaque pathology. These results are further supported by our recent data  showing that timely, short-term therapies that  interfere with immune cell function may be beneficial in AD (Zenaro et al., 2015).

    Treg cells suppress the immune system through antigen-dependent as well as antigen-independent mechanisms. Finding an increase of Treg cells in secondary lymphoid organs in 5XFAD mice is an important observation and it would be interesting to investigate if the peripheral increase of Tregs is antigen-independent or is related to expansion due to CNS or non-CNS antigens.

    Previous data have shown that CD4+ regulatory T cells do not only suppress adaptive T cell responses, but are also able to inhibit the functions of monocytes and macrophages in vitro and in vivo (Taams et al., 2005; Maloy et al., 2003). Thus, it would be relevant to further characterize the nature of the interplay between monocytes-macrophages and Tregs that migrated into the brain and seem beneficial in the AD model Baruch et al. used.

    The 5XFAD mice display a rapid and aggressive model of Aβ pathology and the relevance of the findings need to be confirmed in other animal models of AD. 


    . Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin. Nat Med. 2015 Aug;21(8):880-6. Epub 2015 Jul 27 PubMed.

    . Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells. Hum Immunol. 2005 Mar;66(3):222-30. PubMed.

    . CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms. J Exp Med. 2003 Jan 6;197(1):111-9. PubMed.

    View all comments by Gabriela Constantin
  2. This work convincingly demonstrates that systemic immune suppression can regulate cerebral immune defenses, at least in part by modulating immune cell trafficking to the central nervous system. This is an exciting and innovative concept in the field. It is a bit counterintuitive that by interfering with T regulatory cells (Tregs) you end up with more immune suppression in the brain, but this only highlights how little we understand the mechanisms of the immune system in brain.

    These findings further confirm that the brain is far from being an immune-privileged site, and its homeostasis crucially depends on the proper functioning of the whole immune system. I agree with the authors that modulating the adaptive immune system to induce a beneficial immune response (by peripheral macrophages as well as by microglia) is an attractive therapeutic possibility for AD. 

    To this end, however, it remains to be clarified whether the problem lies in the periphery or at the local level (i.e., infiltrating-patrolling T cells), and how the two systems cross-talk during disease progression. Dysregulation of the adaptive immune system in AD has been proposed, however, results from blood analysis so far have been inconsistent in support (nicely reviewed by Town, 2005). In fact, the evidence for increased Tregs in AD is sparse; on the other hand, a recent paper found even higher activation of CD8 cells in CSF of mild AD patients compared to healthy elderly controls (Lueg et al., 2015). While other work suggests increased activation of infiltrating T cells in brains of aged APP-PS1 mice (Browne et al., 2013), our group has recently observed signs of immunosuppression in the brains of two independent APP-tg mice models in the absence of major systemic changes at very advanced stages of the pathology (15- to 24-month-old mice), thus indicating a local rather than global immunomodulatory effect of Aβ pathology (presented at the last AD/PD, papers under revision). Adaptive immune activation levels most likely change with age and disease progression; whether any of the above preclinical results holds true in AD patients remains to be established.

    In summary, the paper from Baruch et al. centered on a crucial and yet overlooked aspect of AD pathology; I hope that its publication will fuel more basic and clinical research to clarify the local and systemic adaptive immune response to AD pathology.


    . T-cells in Alzheimer's disease. Neuromolecular Med. 2005;7(3):255-64. PubMed.

    . Clinical relevance of specific T-cell activation in the blood and cerebrospinal fluid of patients with mild Alzheimer's disease. Neurobiol Aging. 2015 Jan;36(1):81-9. Epub 2014 Aug 23 PubMed.

    . IFN-γ Production by amyloid β-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer's disease. J Immunol. 2013 Mar 1;190(5):2241-51. PubMed.

    View all comments by Maria Teresa Ferretti

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