Wednesday, 31 May 2017

T regs

Barsheshet Y, Wildbaum G, Levy E, Vitenshtein A, Akinseye C, Griggs J, Lira SA, Karin N. CCR8+FOXp3+ Treg cells as master drivers of immune regulation. Proc Natl Acad Sci U S A. 2017. pii: 201621280.

The current study identifies CCR8+ regulatory T cells (Treg cells) as drivers of immunosuppression. We show that in human peripheral blood cells, more than 30% of Treg up-regulate CCR8 following activation in the presence of CCL1. This interaction induces STAT3-dependent up-regulation of FOXp3, CD39, IL-10, and granzyme B, resulting in enhanced suppressive activity of these cells. Of the four human CCR8 ligands, CCL1 is unique in potentiating Treg cells. 


The relevance of these observations has been extended using an experimental model of multiple sclerosis [experimental autoimmune encephalomyelitis, (EAE)] and a stabilized version of mouse CCL1 (CCL1-Ig). First, we identified a self-feeding mechanism by which CCL1 produced by Treg cells at an autoimmune site up-regulates the expression of its own receptor, CCR8, on these cells. Administration of CCL1-Ig during EAE enhanced the in vivo proliferation of these CCR8+ regulatory cells while inducing the expression of CD39, granzyme B, and IL-10, resulting in the efficacious suppression of ongoing EAE. The critical role of the CCL1-CCR8 axis in Treg cells was further dissected through adoptive transfer studies using CCR8-/- mice. Collectively, we demonstrate the pivotal role of CCR8+ Treg cells in restraining immunity and highlight the potential clinical implications of this discovery.

Some bedtime reading for those interested

6 comments:

  1. No comments?....Another hole in the "Black swan"?
    No B cells this time
    I have no access to the paper but is the really new stuff ?
    A number of recent immunological studies
    have provided the proof-of-concept that a chronic autoreactive
    immune system can indeed be ‘reset’ into a naive and self-tolerant
    immune system. These data include the regeneration of naive B
    cells,5,11 thymic reactivation,5,12–14 the emergence of a polyclonal
    TCR repertoire5,12,14 and restoration of Foxp3+ regulatory T-cell
    (Treg) levels.15,16
    From the EBMT Bone Marrow Transplantation (2015)

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    1. We will be seeing the swan this month no doubt

      I didn't have the time to create links to CCCL1 and it is rather straight forward in that it says Important T regs contain this chemokine. It may be of interest to some but not to many.

      The first question is are these T regs important in MS?

      If they are how does daclizumab work, given it is depleting T regs?

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  2. Perhaps it has more relation with the black swan than one imagines ...

    https://www.ncbi.nlm.nih.gov/pubmed/19319950

    https://www.era.lib.ed.ac.uk/handle/1842/2680

    https://www.ncbi.nlm.nih.gov/pubmed/25717101

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    1. Thanks for this

      Regulatory T cells (T(reg)) provide a balance to immune T cell activation thereby protecting the body from pathogen-induced immunopathology. Several persistent viruses induce T(reg) that subvert protective immune mechanisms and promote viral persistence. Epstein-Barr virus (EBV) generally infects children subclinically and persists thereafter, but primary infection in early adulthood may cause immunopathological damage manifest as infectious mononucleosis. In this study the role of T(reg) was investigated in acute infectious mononucleosis and healthy EBV seropositive donors. The proportion of CD4(+)CD25(high) T cells in blood from infectious mononucleosis patients was significantly lower than in seropositive donors (P = 0.05). Using the FOXP3 marker for T(reg) the same frequency and extra-follicular distribution of T(reg) was noted in infectious mononucleosis and control tonsils. Regulatory cytokines, interleukin (IL)-10 and transforming growth factor (TGF)-beta, were significantly raised in infectious mononucleosis compared to seropositive donor plasma (P = 0.0001, P = 0.0004 respectively) although levels of IL-10 peaked earlier in infectious mononucleosis than TGF-beta. Previous studies identified EBV latent membrane protein (LMP)-1-induced T(reg) activity [Marshall et al. (2003): J Immunol 170:6183-6189; Marshall et al. (2007): Brit J Haematol 139:81-89], and in this study a significant reduction in interferon-gamma production was found from infectious mononucleosis but not seropositive donor lymphocytes after stimulation with a recall antigen when LMP-1 peptide PRG was added (P = 0.03). It is possible that T(reg) are important in controlling primary EBV infection to a subclinical level in most cases and that infectious mononucleosis represents a failure of this protective mechanism.


      MPORTANCE:
      Most humans are infected with Epstein-Barr virus (EBV), a cancer-causing virus. While EBV generally persists silently in B lymphocytes, periodic lytic (re)activation of latent virus is central to its life cycle and to most EBV-related diseases. However, a substantial fraction of EBV-infected B cells and tumor cells in a population is refractory to lytic activation. This resistance to lytic activation directly and profoundly impacts viral persistence and the effectiveness of oncolytic therapy for EBV(+) cancers. To identify the mechanisms that underlie susceptibility to EBV lytic activation, we used host gene and protein expression profiling of separated lytic and refractory cells. We find that STAT3, a transcription factor overactive in many cancers, regulates PCBP2, a protein important in RNA biogenesis, to regulate susceptibility to lytic cycle activation signals. These findings advance our understanding of EBV persistence and provide important leads on devising methods to improve viral oncolytic therapies.

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    2. You're welcome, MD.
      I have randomly read about EBV and talked to some friends of my who are oncologists.

      Perhaps in the field of MS if Neurology were to join in research with Oncology more answers and more quickly we would have to what EBV is able to do in an organism depending on the genetic variants found. I think the work done by Barts and Team G and the recent study led by Dr. Michael Pender have demonstrated that there is rather visible evidence that EBV is implicated in the pathology of MS.
      So focusing efforts on understanding what is happening may be the best and only way for us to come to a verdict about the exact cause of the disease and the really effective medications against all stages / forms of MS.

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    3. LMP-1 is considered an oncogene. Its expression results in increased levels of CD23, which is a B-cell activation antigen. LMP-1 also induces expression of bcl-2, an inhibitor of apoptosis in infected cells. LMP-2 prevents EBV reactivation in latently infected cells. EBNA-1 maintains the episomal configuration of the latent virus. EBNA-2 up-regulates the expression of LMP-1 and LMP-2, which are necessary for transformation of the B cell.

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