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


 

Microbiota drives airway IgA class switch via DC-derived TGF-β

IgA is a class of antibody specifically designed for protection and tolerance at mucosal surfaces. Since vast majority of antigens [both infectious or noninfectious nature] interact with mucosal tissues, knowledge of signals controlling IgA production would help to develop more robust vaccination protocols.

So I decided to review this paper from Journal of Experimental Medicine where the authors have analysed IgA promoting capacity of lung DCs.

Most experiments were done ex vivo on sorted DC and B cells. Most cultures included α-IgM and α-CD40 antibody to "mimic" T-dependent Ab production. First, the authors noticed that lung CD103⁺ and CD24⁺ DCs (but not CD64⁺ Mφ) could provide necessary signals to naive B cells to switch to IgA (similar to MLN DCs).

Next, the authors found that this IgA switch capacity of lung CD103⁺ and CD24⁺ DCs  were dependent of their ability to produce TGF-β and Retinoic Acid (Vitamin A metabolites).

Next, the authors found that microbiota influenced lung DCs capacity to drive IgA switch in naive B cells [though it is not clear whether it is airway or gut microbiota that does it].

Follow up experiments revealed that MyD88/TRIF signaling [most likely from microbiota] in lung DC cells increased TGF-β production and their IgA switch potential.

Finally, the authors showed that i.n (intra-nasal) or i.t. (intra-tracheal) immunization [but not s.c. immunization] with small dose of cholera toxin (CT) provided system-wide protection against cholera toxin re-challenge, implying body-wide re-distribution of airway primed CT-specific B cells.

In summary, this study showed the role of microbiota/MyD88/TGF-β/CD103⁺ DCs axis in driving airway mucosal IgA class switch.

David Usharauli