Monday, December 19, 2011

Too good to be to true

Currently, Foxp3+ CD4 T cells, also known as regulatory T cells (Tregs), are most studied and still least understood T cell subset. Why is that? The main challenge to Tregs/suppressor concept is that they do not fit in any mainstream theoretical framework of immune system organization. In absence of such working model, translation of basic Tregs research into clinical practice will look as sporadic efforts with no real progress and consensus.

If you are interesting to know more about Tregs, I will recommend reading following article published in journal Nature few weeks ago. This study by Michael Rosenblum et al. (1), exactly represents that confusion typical to Tregs research. First, this is a fairly simple study and we may applaud Nature for taking step to publish a research paper that does not include highly expensive (in many cases completely irrelevant or useless) experimental methods. Actually I see some pattern in this direction from Nature's editorial board. Nature started to publish simple papers (the most recent example of this kind is a research article about dendritic cells and lymph node-specific high endothelial venules). However, simplicity is not the same as significance or relevance.

In this new article by Michael Rosenblum et al., the authors created mice that will express OVA antigen in the skin only upon treatment with a doxycycline and crossed them to the mice transgenic for OVA-specific T cell. In absence of doxycycline, this modified mice have healthy skin, and harbor substantial population of OVA-specific Tregs (due to doxycycline-independent thymic expression of OVA). Within 5-10 days upon doxycycline treatment, the skin becomes highly inflamed due to OVA-specific T cell effector infiltration. However, within 40-60 days skin inflammation is completely resolved. How? The authors suggested that it has to do with Tregs, because Tregs depletion led to more severe skin inflammation. The problem is that even in condition of Tregs depletion, the skin inflammation is still resolved and almost within the same time frame as in presence of Tregs (Fig 2a, e, g). In general, Tregs depletion with anti-CD25 antibody may not eliminate all Tregs, so this particular experiments are not optimal approaches. This leave open the main question what is the role of Tregs in this process. In Fig. 4E, f, the authors showed that when expression of OVA is turned off for 20-30 days and then turned on again, skin inflammation that developed 2nd time is less severe and is resolved at faster rate compared to initial skin inflammation in the same mice. The authors showed that after resolution of initial skin inflammation, there were more Tregs retained in the skin and these Tregs were more potent in suppressing naïve T cells proliferation. The authors conclusion is that tissue (skin) maintains memory Tregs specific to initial antigen and their presence is required to resolve skin inflammation.

Essentially, the authors idea is that similar to effector T cells, Tregs also undergo the same phases of a typical immune response: activation, expansion, memory differentiation. In my opinion, the data to support this claim are weak. First, Tregs depletion should have been done with Foxp3-DTR mice to selectively deplete Foxp3+ T cells and second, no data is provided to show that initial OVA expression and inflammation does not select for skin epithelial cells expressing less of OVA that may have explained reduced inflammation upon re-expression of OVA in the skin.


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