## Archive for December, 2011

### IPEX and CD25

December 20, 2011

In a recent post I wrote about some ideas of Kendall Smith and his role in discovering the cytokine IL-2. On 8th December I heard him give a talk in which he presented various ideas about IL-2, its receptor and Tregs. I discussed some aspects of IL-2 in the last post. When mutant mice are engineered which cannot produce IL-2 they show a strange combination of symptoms which combine immunodeficiency (a reduced capability of the immune system to fight pathogens) and autoimmune disease (an inappropriate reaction of the immune system to host tissues). This probably has to do with the fact that IL-2 is important for the production of both effector T cells and Tregs, which act in opposite directions. Similar phenomena are seen in the disease of humans called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome). It is often attributed to a lack of the transcription factor Foxp3 which is of central importance for the function of Tregs. The gene for Foxp3 is on the X chromosome and this explains the way IPEX is inherited and the term X-linked in its name. However, as pointed out by Smith in his talk, one third of patients diagnosed with IPEX have no mutation in the Foxp3 gene. In this context he referred to a paper of Caudy et al. (J. Allergy Clin. Immunol. 119, 482). What is shown in this paper is that there is a different possible cause of IPEX-like symptoms, namely mutations in the gene for CD25, a surface molecule associated to Tregs.

The paper concerns a patient (an eight year old boy) who had suffered a horrific combination of diseases. It was found that he had mutations in both copies of the CD25 gene. The mutation in one copy came from the mother and was a frame shift due to an insertion. In other words, there is a extra base in the DNA which makes the part of the gene after it look like nonsense when it is being transcribed. The mutation in the other copy came from the father and consisted of one base being exchanged. This happed to cause a stop codon so that reading stopped at that point. The combination of these circumstances meant that the boy could not produce CD25 and this was the presumed cause of his disease. His Foxp3 gene was normal. On the other hand other IPEX patients can produce CD25. Thus there appear to be two diseases with related symptoms. The gene coding for CD25 is on chromosome 10, not the X chromosome. This is why two mutations are necessary to produce CD25 deficiency.

What is the connection to IL-2? The IL-2 receptor, which was also discovered by Kendall Smith and his collaborators, consists of three chains called $\alpha$, $\beta$ and $\gamma$. The second and third are always present on the surface of T cells but the first is only present in variable amounts. In fact the $\alpha$ chain of the IL-2 receptor is nothing other than CD25. The $\beta$ and $\gamma$ chains together allow for some IL-2 signalling but strong signalling in response to normal concentrations of IL-2 is only possible with the help of the $\alpha$ chain. In this case it is not only the case that the receptor signals when IL-2 is bound to it. Binding also causes the receptor to be taken into the interior of the cell and destroyed. This process is an important part of the dynamics associated to IL-2. The $\gamma$ chain of the IL-2 receptor also forms part of the receptor for many other cytokines, for instance IL-4. The gene for this receptor is on the X chromosome. When it cannot be produced due to a mutation this leads to a disease called X-linked severe combined immunodeficiency (SCID). In this case the immune system does not function since so much of its signalling system has been disrupted. This is also known as the ‘bubble boy disease’ since children affected by it have to live in a sterile environment.

### Shifting attention towards Tregs

December 3, 2011

Yesterday I heard a talk by Abul Abbas where two of the main themes were regulatory T cells (Tregs) and interleukin 2. Correctly functioning immunity is the result of a balance between effector cells and Tregs and he emphasized that in trying to develop therapies it might be more valuable to concentrate on influencing the regulatory side. He described a mouse model which he has developed for studying autoimmune disease. One criterion in developing this model was that it should concern the target tissue where an antigen is expressed and not the lymphoid tissue. Another is that the target tissue should be easily accessible for doing experiments in vivo. For this reason he chose the skin. In this transgenic model antigen expression can be turned on and off by feeding the mice with doxycyclin. When the antigen is turned on an autoimmune disease results. If it is turned off the mice recover. If it is turned on again the mice get sick again but much less than the first time. This is reminiscent of ordinary immunity which is due to memory effector cells. In this case it seems that there are memory Tregs. This suggests the idea that a possible cause of autoimmune disease in humans could be a lack of memory Tregs.

When IL-2 was first discovered it was known for causing T cells to proliferate and thus strengthening the immune response. More recently it has been found that eliminating IL-2 does not necessarily act in an immunosuppressive way. Apparently it can be replaced by something else in driving the proliferation of effector T cells. On the other hand it also drives the proliferation of Tregs and Abbas argued that this is its most essential function. In that case it cannot be replaced.

The lecturer made a number of interesting comments about themes such as immunology, therapies for immune disorders and cancer, clinical trials etc. I did not note them down and I cannot reproduce them here. Nevertheless I have the impression that a learned of lot of things which I might profit from in the future.