Foxp3+ T cell deficiency leads to lethal immunopathology in mice and severe organ pathology in humans (IPEX syndrome). Over the past 20 years numerous mechanisms of action of Foxp3+ T cells have been described. In fact, this number is so numerous that it wouldn't be a "heresy" from my part to claim that no single Foxp3+ T cell phenotype could explain it. This leaves us with the hypothesis that multiple versions of Foxp3+ T cells exist, each of them using selective path for immune regulation and suppression.
With this view in mind, it was useful to read a new paper from Rudensky's lab published in journal Cell this week that provided evidence showing the role of Foxp3-positive T cell-specific amphiregulin in preventing excessive tissue pathology during high dose of viral infection.
First, the authors verified that amphiregulin, an epidermal growth factor family member, was expressed by Foxp3+ T cells.
Next, the authors showed that amphiregulin deficient Foxp3+ T cells displayed normal suppressive functionality when transferred into T cell-deficient host.
Further experiments revealed that amphiregulin deficiency in Foxp3+ T cells did not modify the host immune response to intranasal flu infection (mouse PR8 model).
However, the authors noticed that there was excessive lung tissue damage in response to high (but not low) dose of flu infection in the hosts with Foxp3+ T cell-specific deletion of amphiregulin.
Finally, the authors showed that amphiregulin up-regulation was primarily restricted to IL-18R+ Foxp3+ T cells.
In summary, these data tend to reinforce the idea that Foxp3+ T cells could function in a tissue selective manner and are most likely controlled by tissue environment as suggested by Polly Matzinger and Tirumalai Kamala. This could explain why there are so mechanisms of suppression by Tregs, at least one mechanism for each tissue.
What are some of the weaknesses of this study? First, injection of amphiregulin to hosts with Foxp3+ T cell-specific deletion of amphiregulin would have been useful. Second, data regarding IL-18R deficient Foxp3+ T cells could have provided in vivo confirmation for this study (the authors simply mentioned that they have done experiments with bone marrow chimera to test the role of IL-18R in amphiregulin up-regulation and that it supported their conclusions).
Why is this study important? Because without our mastery of Foxp3+ T cell biology we will not be able to make any major, predictable advances in treating human immune related conditions (cancer, allergy, autoimmune conditions).
David Usharauli
With this view in mind, it was useful to read a new paper from Rudensky's lab published in journal Cell this week that provided evidence showing the role of Foxp3-positive T cell-specific amphiregulin in preventing excessive tissue pathology during high dose of viral infection.
First, the authors verified that amphiregulin, an epidermal growth factor family member, was expressed by Foxp3+ T cells.
Next, the authors showed that amphiregulin deficient Foxp3+ T cells displayed normal suppressive functionality when transferred into T cell-deficient host.
Further experiments revealed that amphiregulin deficiency in Foxp3+ T cells did not modify the host immune response to intranasal flu infection (mouse PR8 model).
However, the authors noticed that there was excessive lung tissue damage in response to high (but not low) dose of flu infection in the hosts with Foxp3+ T cell-specific deletion of amphiregulin.
Finally, the authors showed that amphiregulin up-regulation was primarily restricted to IL-18R+ Foxp3+ T cells.
In summary, these data tend to reinforce the idea that Foxp3+ T cells could function in a tissue selective manner and are most likely controlled by tissue environment as suggested by Polly Matzinger and Tirumalai Kamala. This could explain why there are so mechanisms of suppression by Tregs, at least one mechanism for each tissue.
What are some of the weaknesses of this study? First, injection of amphiregulin to hosts with Foxp3+ T cell-specific deletion of amphiregulin would have been useful. Second, data regarding IL-18R deficient Foxp3+ T cells could have provided in vivo confirmation for this study (the authors simply mentioned that they have done experiments with bone marrow chimera to test the role of IL-18R in amphiregulin up-regulation and that it supported their conclusions).
Why is this study important? Because without our mastery of Foxp3+ T cell biology we will not be able to make any major, predictable advances in treating human immune related conditions (cancer, allergy, autoimmune conditions).
David Usharauli
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