Tregs muscle up in the periphery

There is still a lot of confusion regarding role of peripherally generated Foxp3+ Tregs. Data so far indicate that peripherally induced Tregs play limited [if any] role in maintaining check on auto-reactive T cells. However, extra-thymic Treg population could prevent "excesses" of other T helper class differentiation.

For example, transcription factor, Musculin, ordinarily found in muscle cells, appears to stabilize Foxp3+ Tregs phenotype at the mucosal surfaces.  

High level of Musculin expression was detected in in vitro induced Foxp3+ Tregs (iTregs).

Musculin deficient mice harbor fewer Tregs at gut mucosal sites.

Musculin deficiency in T cells shifted their differentiation pathway from Foxp3+ Tregs into Th2 cells.

Indeed, removal of canonical Th2 cytokine IL-4 reversed such Th2 shift in Musculin deficient T cells under iTreg differentiation setting.

Musculin deficient iTregs also failed to inhibit house dust mite allergen induced inflammation in lungs upon adoptive transfer.

For me these data confirm that stability of extra-thymic Foxp3+ T regs in the periphery requires coordinated action of several factors, one of which, appears to be Musculin. Musculin prevents excessive Th2 differentiation in settings that may favor local Tregs generation. Extra-thymic Treg differentiation pathway does not appear to play a significant role in maintaining peripheral tolerance. Rather, their role is mostly, in my view, consist of absorbing and neutralizing any "excesses" in T helper differentiation, in this case Th2 pathway.

David Usharauli