Thursday, 20 February 2014

So Long FoxP3? Here comes FoXA1 a new regulatory immune cell. Another or the mechanism for beta interferon

Liu Y, Carlsson R, Comabella M, Wang J, Kosicki M, Carrion B, Hasan M, Wu X, Montalban X, Dziegiel MH, Sellebjerg F, Sørensen PS, Helin K, Issazadeh-Navikas S. FoxA1 directs the lineage and immunosuppressive properties of a novel regulatory T cell population in EAE and MS.Nat Med. 2014 Feb. doi: 10.1038/nm.3485. [Epub ahead of print]

The defective generation or function of regulatory T (Treg) cells in autoimmune disease contributes to chronic inflammation and tissue injury. We report the identification of FoxA1 as a transcription factor in T cells that confers suppressive properties in a newly identified Treg cell population, herein called FoxA1+ Treg cells. FoxA1 bound to the Pdl1 promoter, inducing programmed cell death ligand 1 (Pd-l1) expression, which was essential for the FoxA1+ Treg cells to kill activated T cells. FoxA1+ Treg cells develop primarily in the central nervous system in response to autoimmune inflammation, have a distinct transcriptional profile and are CD4+FoxA1,+CD47,+CD69,+PD-L1hig, FoxP3-. Adoptive transfer of stable FoxA1+ Treg cells inhibited experimental autoimmune encephalomyelitis in a FoxA1-and Pd-l1-dependent manner. The development of FoxA1+ Tregcells is induced by interferon-β (IFN-β) and requires T cell-intrinsic IFN-α/β receptor (Ifnar) signaling, as the frequency of FoxA1+ Treg cells was reduced in Ifnb-/- and Ifnar-/- mice. In individuals with relapsing-remitting multiple sclerosis, clinical response to treatment with IFN-β was associated with an increased frequency of suppressive FoxA1+ Treg cells in the blood. These findings suggest that FoxA1 is a lineage-specification factor that is induced by IFN-β and supports the differentiation and suppressive function of FoxA1+ Treg cells.

This study identifies Forkhead box protein A1 (FOXA1) a transcription factor bound to programmed cell death 1, which can control T cell responses and allows Treg to kill activated T cells and so quells and dampens immune responses. These are distinct from the FoxP3+ T reg cells implicated in stopping the generation of autoimmunity. 

These cells are stimulated by beta interferon as shown by a number of knockout studies. Could this be how beta interferon works in humans? 

They show that beta interferon increased these cells in people treated with drug.  However, if this is the activity then we have to say that it could do better, as beta interferons are not completely effective in MS. However very interesting a new cell is born. 

P.S. I wonder if Glatiramer acetate also stimulates these cells as a new MOA:-)

p.p.s. for those reading the actual paper  I had a look at scoring system, surprisingly not mentioned in the paper-maybe I missed it, in the reference supplied. The EAE scoring system based on reference ranges from 0-8 . 0 = Normal, 1 is tail weakness, 2 = limp tail.  Most EAE experiments controls in this paper range from 0.5-2 so influences are from not much of a tail problem to more or less of a tail problem.

1 comment:

  1. So far there are natural Treg (nTreg) which come out of the thymus and adaptive Greg (aTreg) which are formed in the periphery. aTreg may or may not have FoxP3 as a marker. So where do these cells fit (nTreg or aTreg)?


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