Science Signaling Podcast: 27 November 2012

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Science Signaling  27 Nov 2012:
Vol. 5, Issue 252, pp. pc27
DOI: 10.1126/scisignal.2003763


This Podcast features an interview with Rose Zamoyska, senior author of a Research Article that appears in this issue of Science Signaling. Zamoyska’s group has investigated the role of the protein tyrosine phosphatase PTPN22 in autoimmunity. The balance of immune cell activity is important for keeping the immune system functioning properly, and autoimmune disease can result when effector T cells are overly active or when regulatory T cells, which inhibit effector T cell responses, are less active. PTPN22 has been implicated in autoimmune disease in humans, but mice lacking this phosphatase do not develop spontaneous autoimmunity. The study by Brownlie et al. revealed that, although PTPN22-deficient mice had greater effector T cell activity than wild-type mice, their regulatory T cells also exhibited greater immunosuppressive activity. These findings explain why PTPN22-deficient mice do not develop spontaneous autoimmunity and suggests that PTPN22 could be targeted for treating autoimmune disease.

(Length: 13 min; file size: 7.3 MB; file format: mp3; location: http://podcasts.aaas.org/science_signaling/ScienceSignaling_121127.mp3)

Technical Details

Length: 13 min

File size: 7.3 MB

File Format: mp3

RSS Feed: http://stke.sciencemag.org/rss/podcast.xml

Listen to Podcast: http://podcasts.aaas.org/science_signaling/ScienceSignaling_121127.mp3

Educational Details

Learning Resource Type: Audio

Context: High school upper division 11-12, undergraduate lower division 13-14, undergraduate upper division 15-16, graduate, professional, general public and informal education

Intended Users: Teacher, learner

Intended Educational Use: Learn, teach

Discipline: Cell biology, immunology, human biology,

Keywords: Science Signaling, autoimmune disease, autoimmunity, effector T cell, immnuosuppression, phosphatase, PTPN22, regulatory T cell, Treg


Host – Annalisa VanHookWelcome to the Science Signaling Podcast for November 27th, 2012. I’m Annalisa VanHook, and today I’ll be speaking with Rose Zamoyska, senior author of a paper that appears in this week’s issue of Science Signaling (1) about how the loss of a phosphatase affects autoimmunity.

The immune system protects us from disease by attacking foreign invaders such as bacteria and viruses, and by ridding the body of abnormal cells that have become cancerous or infected by pathogens. Autoimmunity occurs when the immune system attacks the cells of the self, and it can result from an imbalance in the activities of various types of immune cells. For example, effector T cells perform functions that can either directly or indirectly lead to the elimination of infected or tumorigenic cells. They may kill the target cells themselves or activate other types of immune cells that actually do the killing. Overactivation of these effector T cells can lead to autoimmunity. Whereas effector T cells promote the immune response, regulatory T cells have an immunosuppressive effect. Regulatory T cells suppress the functions of other types of immune cells—including the effector T cells—and so they limit the immune response. Autoimmunity can arise when regulatory T cells are less able to perform their normal functions. And so, autoimmunity can arise when effector T cells are overactive or when regulatory T cells are less active.

The phosphatase PTPN22 has been implicated in regulating T cell function, and mutations in the gene that encodes this phosphatase have been linked to increased risk of developing autoimmune disease. Zamoyska’s group has investigated the function of PTPN22 in mice, and they’ve found that its absence promotes the activities of both effector and regulatory T cells. Zamoyska spoke to me by telephone from the University of Edinburgh.

Interviewer – Annalisa VanHookWelcome, Dr. Zamoyska.

Interviewee – Rose ZamoyskaThank you.

Interviewer – Annalisa VanHookMutations in the gene that encodes this phosphatase, PTPN22, have been associated with an increased risk for developing autoimmune disease in humans. But, in mice, it’s been reported that the mice lacking this gene don’t necessarily develop autoimmune disease. Do the PTPN22 knockout mice develop autoimmune disease at a higher rate than control mice? Do they show increased risk similar to what’s seen in humans?

Interviewee – Rose ZamoyskaWell, it’s surprising that PTPN22−/− mice don’t develop spontaneous autoimmune disease at a higher rate than control mice. However, our mice live in a very protected, superclean environment, so they’re not subjected to infections in the same ways that humans are. So the immune system of our mice might not get the same triggers that would push them into a situation that’s going to predispose them to autoimmunity. But we do have some indication that if we experimentally induce autoimmunity, then we can see an increased rate of autoimmunity in the PTPN22 knockout mice.

Interviewer – Annalisa VanHookWhat happens to the immune systems of mice when PTPN22 is knocked out? Even if you don’t induce autoimmunity, how is their immune system different from normal mice?

Interviewee – Rose ZamoyskaWell, the effector T cells in these mice seem to be much more easy to stimulate, and they make more cytokines—and these are molecules that are very important in inflammation, and they drive immunoglobulin production. And it was shown in previous studies that the PTPN22 knockout mice do have an increase in serum immunoglobulin compared to control mice. And actually it’s very interesting that in humans, anti-B-cell depletion therapy is used a lot in autoimmunity these days, and that very effectively depletes serum immunoglobulin. So, we don’t entirely understand how the B-cell depletion therapy works to prevent autoimmunity, but it’s looking very promising.

Interviewer – Annalisa VanHookYour starting point for this study was generating these PTPN22 knockouts and looking more closely at their immune systems. What’s going on in the immune systems of those mice?

Interviewee – Rose ZamoyskaWell, the PTPN22 knockout mice that we generated were confirmed the previous results, which is that numbers of effector T cells were up in these mice. But our new finding is that these mice also have an increase in this particular population of cells that are called Tregs, or regulatory T cells. And the Tregs are very important in regulating immune responses and particularly in autoimmune responses, so we wondered whether the reason that the mice don’t get spontaneous autoimmunity is because their Tregs are super efficient.

Interviewer – Annalisa VanHookThe Tregs are very efficient at shutting down the sort of immune responses that would lead to autoimmunity.

Interviewee – Rose ZamoyskaExactly, yes.

Interviewer – Annalisa VanHookHow do the regulatory T cells from these knockout mice compare to the regulatory T cells from normal mice?

Interviewee – Rose ZamoyskaWell, the way we looked at that was to do an experiment where you can purify naïve T cells, which are cells haven’t responded to anything, and transfer them on their own into a mouse which has no immune system of its own. And in that environment, the cells will expand, and the mice will develop an inflammatory bowel condition. So, if you take the cells from a normal mouse and you mix them with normal Tregs, you’ll prevent this expansion, and you’ll prevent the inflammatory bowel condition. If we do the same thing with cells from our PTPN22 knockout mice—we take the effector cells and transfer them—we find the mice get much more aggressive disease. But again, we can prevent that with the Tregs from the knockout mice. But the really interesting point was that if we tried to prevent disease from knockout effector cells with wild-type—or normal—Tregs, they weren’t able to prevent the knockout effector cells from causing disease. So that showed that the knockout Tregs are really much better than normal—or wild-type—Tregs.

Interviewer – Annalisa VanHookThe effector T cells in the knockout mice are easier to activate and so more prone to cause autoimmune disease. But the regulatory T cells are better at shutting down those responses that could lead to autoimmunity. How is PTPN22 having these apparently opposite effects on different types of cells, or is it just making both types of cells easier to activate?

Interviewee – Rose ZamoyskaNo, we think it’s actually doing different things to the two types of cells. So, one of the things that happens with T regulatory cells is they don’t use exactly the same mechanisms that effector cells use. And the PTPN22 knockout Tregs have more on their surface of a molecule which is called an integrin. And integrins are really important for getting cells to stick together. And other groups have found that integrins are essential for Treg activity. So, when Tregs are activated, the integrins change their structure, and they bind much better. And we think that not having PTPN22 makes it happen more efficiently. And a very interesting thing that was discovered by other groups is that Tregs specifically turn down the amount of PTPN22 they have in the cell compared to the amount you’d find in effector T cells. And that suggests that Tregs work better if they have less PTPN22, and that fits exactly with our findings that having no PTPN22 makes the Tregs work better still.

Interviewer – Annalisa VanHookDo you know how the lack of PTPN22 is causing the effector T cells to be more easily activated?

Interviewee – Rose ZamoyskaWell, for the effector T cells, the important thing there is that they’re stimulated through their T cell receptor, which is the molecule that recognizes foreign antigens. And the signals that come through this receptor are modulated—so they’re kept down—by PTPN22, which is why we think there’s more PTPN22 in effector T cells because on the whole they’re easier to activate. So if you don’t have the PTPN22 present in the effector T cells, they become even easier to activate, and self molecules that wouldn’t normally cause them to be activated now may be able to trigger them to make a response.

Interviewer – Annalisa VanHookSo, when we’re talking about autoimmunity and animal models of autoimmunity, we automatically start thinking about whether or not these findings can be transferred into humans for the treatment of autoimmune disease. But given the fact that PTPN22 seems to have sort of opposite functions on Tregs and T effector cells, do you think that these findings could be translated into humans in the context of treating autoimmune disease?

Interviewee – Rose ZamoyskaWell, Tregs are clearly important in controlling autoimmunity in people. And one of the things that we really hope will happen is that our findings will stimulate new studies into exactly what’s going on in the Tregs of autoimmune individuals that have this PTPN22 variant protein because there’s really nothing being published on that at the moment. But the other thing is that you can think about the relationship between effector T cells and Tregs as a sort of arms race. So, effector T cells get ahead when there’s infectious agents around that need removing, but then the Tregs catch up once the infection is gone and restore the system back to an even keel. So if this arms race gets out of balance, that’s when you can end up with problems such as autoimmunity. And so it’s interesting because there are some studies that are looking at the potential of Treg immunotherapy, particularly in clinical transplantation settings. And here they expand Tregs in tissue culture, and then they’re giving them back to patients. So, our studies suggest that there may be ways to manipulate Tregs to make them more effective. So it would be really exciting to see whether or not this knowledge in the future can be used to manipulate Tregs for these kinds of studies and then translate them into better therapy.

Interviewer – Annalisa VanHookSo you’re thinking about, then, the possibility of taking Tregs out of a patient, modifying them in vitro, expanding them, and then putting them back in?

Interviewee – Rose ZamoyskaYes, that would be the kind of approach that I think people are working at, particularly, as I said, in the transplant setting and possibly even in autoimmune settings. Because as you said, the problem otherwise is if you tried to knockdown PTPN22 in an individual you’d make the effectors better, as well as the Tregs better, so you have to be able to manipulate these two populations independently of each other. But there is the possibility of doing that in a tissue culture setting first and then putting the cells back into people.

Interviewer – Annalisa VanHookThank you, Dr. Zamoyska, for taking the time to speak with me today.

Interviewee – Rose ZamoyskaYou’re welcome.

Host – Annalisa VanHookThat was Rose Zamoyska, senior author of a paper that appears in the current issue of Science Signaling. That paper is by Brownlie and colleagues and it’s titled “Lack of the Phosphatase PTPN22 Increases Adhesion of Murine Regulatory T Cells to Improve Their Immunosuppressive Function” (1).


And that wraps up this Science Signaling Podcast. If you have any questions or suggestions, you can write to us at sciencesignalingeditors{at}aaas.org. This show is a production of Science Signaling and of AAAS—Advancing Science, Serving Society. I'm Annalisa VanHook, and on behalf of Science Signaling and its publisher, the American Association for the Advancement of Science, thanks for listening.


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