How stable are regulatory T cells?

T cells carrying the surface molecule CD4 are responsible for directing the behaviour of other immune cells. The Th1 and Th2 cells within this class activate the immune response. Inhibitory influences on the immune response come from the regulatory T cells, also known as Treg cells. These carry CD4. It has been recognized that a molecule called Foxp3 is a master regulator of their activity. Foxp3 is a transcription factor, not a surface molecule. Thus it is not so helpful for  identifying these cells experimentally. Yesterday I heard a talk by Shohei Hori from Yokohama on research he and others have done recently on Treg cells. He started by talking about cell differentiation and discussing the issue of whether this always goes in one direction. He recalled that this picture is too simple and that it is known that cells can be induced by artificial means to go backwards in the usual sequence of differentiation or ‘sideways’ onto another branch of the tree of differentiation. A question which arises in this context is whether Treg cells can turn into Th1 cells. This is of medical importance for the following reason. Treg cells might be used for the therapy of autoimmune diseases. If, however, Treg cells given to a patient could turn into Th1 cells this could aggravate the disease. It has been reported that in experimental settings this kind of transformation can take place.

The experimental findings appear contradictory, at least superficially, and a central theme of the talk was how to resolve this conflict. A key idea proposed is that Treg cells are a heterogeneous population. In this view the majority of Treg cells are stable and cannot turn into Th1 cells. At the same time there is a small population called transient Foxp3+ cells which can undergo this kind of transformation. What are the differences between these types? Apparently there is a difference on an epigenetic level with a certain DNA sequence being methylated or not. The ordinary Foxp3+ cells show a high level of expression of the surface molecule CD25 while the transient Foxp3+ cells do not. There remains the question of how the experimental finding of transformation of many Foxp3+ T cells can be reconciled with the relative rarity of the transient Foxp3+ cells. A mechanism for doing this is that under suitable conditions the transient Foxp3+  T cells proliferate in the periphery while the other Foxp3+ cells do not. Once they have proliferated they can transform in relatively large numbers. An open question is how these two types of cell diverge during their development . It may be that this happens before they express Foxp3.

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Systemic lupus erythematosus and NETs

In other posts I have written about autoimmune diseases. These can be divided into those which are specific for one type of tissue and those which are systemic. The latter can affect many tissues. One of the commonest and best-known systemic autoimmune diseases is systemic lupus erythematosus (SLE). It is estimated by the Lupus Foundation of America that there about three and a half million people with this disease worldwide, with ninety per cent of them being women. Caucasians are underrepresented. Yesterday I heard a talk about some aspects of this disease by Virginia Pascual from Texas and this is what stimulated me to write this. Apparently there are few therapeutic possibilites at the moment. She said that no drug has been approved for use against SLE in the last fifty years but that she hopes that this will soon change. At one time the lifespan after diagnosis with this disease was five years. Nowadays, although there is no cure, the disease can be managed so well that with suitable medical care it does not lead to a significant decrease in life expectancy. The severity of the symptoms oscillates in time, with flares and remissions. An important mechanism of pathology in this disease is the accumulation of immune complexes and this leads to a danger of kidney failure. The antibodies forming these complexes are directed against parts of the cell nucleus, in particular DNA.

In the talk the speaker explained a network of mechanisms which are at work in SLE. Some of the key players are interferon , plasmacytoid dendritic cells (pDC’s), the toll-like receptors TLR7 and TLR9 and neutrophils. SLE patients typically have high levels of IFN in the blood and this is not changed by moderate doses of cortisone. It can be turned off by pulse therapy (e.g. 1 g prednisolone per day for 3 days) but it comes back. Under some circumstances it is found that in SLE patients less neutrophils die by apoptosis than in healthy controls. They are dying by another mechanism. This brings us to the NETs (neutrophil extracellular traps) of the title. This concept goes back to a paper of Brinkmann et. al. (Science 303, 1352). It was discovered that neutrophils can eject part of their contents including DNA to form a kind of net which traps bacteria. In fact, as mentioned in the talk yesterday this phenomenon was already observed in lupus patients by Rifkind and Godman in 1957 (J. Exp. Med. 106, 607) but at that time the possibilities of interpreting it were limited. A link between NETs and SLE was suggested in a paper by a group including Arturo Zychlinsky in PNAS in 2010. There it was proposed that in some SLE patients it may happen that NETs produced to combat an infection may be the cause of a flare.

Coming back to therapeutic prospects, it was noted that an inhibitor for TLR7 and TLR9 is under development as a drug against lupus by the company DYNAVAX.