Tuesday, August 22, 2017

Does TGF-β control T cell autoimmunity independent of Tregs?

When T cells attack body's own antigens its called autoimmunity. Each and every one with the adaptive immune system carry this potential. Mostly two mechanisms prevent autoimmunity: thymic deletion of overtly auto-reactive T cells (recessive tolerance) and Foxp3+ Tregs (dominant tolerance).
Within immune system, TGF-β plays important inhibitory role at T cell level. However, since TGF-β is involved in Treg biology, it is not clear if it has Treg-independent role in preventing autoimmunity.
New paper published in PNAS tried to answer this question.
The authors used OT-II RIP-mOva mice model (on RAG KO background) in which all CD4 T cells express OVA-specific T cell receptor and pancreas express OVA protein. These mice harbor OT-II Foxp3+ Tregs and they don't develop autoimmune diabetes.

To separate effect of Tregs versus TGF-β, the authors either compared TGF-βRII-KO mice vs. Foxp3KO (both on RAG1-KO OT-II RIP-mOva background) or adoptively transferred into RAG1-KO RIP-mOVA mice either Foxp3KO OT-II or OT-II T cells expressing TGF-βRII under the control of estrogen receptor. They noticed that OT-II T cell population lacking TGF-βRII but not Foxp3 could cause or accelerate autoimmune diabetes.

These two set of experiments are central for this paper. However, contrary to the authors' conclusions, these experiments do not fully answer Tregs versus TGF-β question. The main problem is that total TGF-βRII deficiency in all CD4 T cells affects both effector and Tregs (functionally at least if not number wise) while Foxp3 deficiency only affects Tregs. That is to say that if Tregs were TGF-βRII-sufficient and effector T cells TGF-βRII-deficient outcome could be different (WT Tregs might be able to stop effector OT-II cells). Another way to separate the role of Tregs versus TGF-β would be to specifically inactivate TGF-βRII in effector T cells leaving Tregs intact.

posted by David Usharauli


1 comment:

  1. For me second part, dealing with the role of Monocytes in Diabetes, is also very interesting. Data are impressive - having 100% (?) of mice diabetic.