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

    

Runx3-dependent intraepithelial lymphocytes (CD4IELs) control gut tolerance to dietary antigens

Few days ago journal Science published another immunological study. This hard to read research paper showed that special subset of Foxp3–CD8αα+CD4+ intraepithelial lymphocytes (CD4IELs) found within intestinal epithelium play distinct and dominant role in preventing gut inflammation to dietary antigens.

It appears that induction or maintenance of Foxp3–CD8αα+CD4+ intraepithelial lymphocytes (CD4IELs) depends on antigens derived from either from gut flora [microbiome] or food.

The main finding of this paper was observation that antigen-specific T cell monoclonal mouse strain deficient for Foxp3 expression [but not Foxp3 wt] depleted of CD4IELs using anti-CD8α antibodies during antigen feeding showed severe intestinal inflammation and diarrhea. It suggests Foxp3–CD8αα+CD4+ intraepithelial lymphocytes (CD4IELs) play distinct and separate [that from Foxp3wt T cells] role in protecting intestinal tissue against antigenic inflammation.

Why is this paper relevant? For one, it indicates that tolerance to food antigens in physiological situations, for example during feeding, could be mediated by Foxp3–CD8αα+CD4+ intraepithelial lymphocytes (CD4IELs), and not by Foxp3+ CD4+ T cells, as scientists ordinarily assume. However, for now, we know relatively little about tissue-resident innate-like or adaptive-like cells, such as these Foxp3–CD8αα+CD4+ intraepithelial lymphocytes (CD4IELs).

David Usharauli