Regulatory T cells need more than Foxp3

Absence of Foxp3+ Tregs leads to uncontrollable activation of self-specific T cells. 

Natural Foxp3+ Tregs are selected in the thymus. This selection is TCR mediated. It is safe to assume that at least in the thymus, TCR transmits signal(s) essential for the induction of Foxp3 protein. 

Does TCR signal have the same function in the periphery as well?

New research published in journal Immunity has examined an effect of TCR ablation on Tregs. To do this, research group led by Marc Schmidt-Supprian have used Mx1-cre TCRalpha fl/fl mice. Mx1 is a IFN-alpha responsive element. IFN-alpha can be induced by Poly(I:C) injection. 

When the authors injected Poly(I:C) into Mx1-cre TCRalpha fl/fl mice they found that ~20% of Foxp3 Tregs lost TCR expression. 

Unexpectedly, examination of TCR-deficient Tregs (tracked by eGFP expression) 6 weeks post treatment revealed that both TCR+ and TCR- Tregs expressed similar level of Foxp3 (both at protein and mRNA level). 

Actually, TCR ablation had effect mostly on molecules which define Tregs' activation phenotype, such as OX40, ICOS, CD44.      

Separate experiments showed that TCR ablation reduced half-life of Tregs.

To examine a consequence of TCR loss on Foxp3+ Tregs' functionality, the authors transferred naive T cells together with Tregs recovered from tamoxifen treated CD4-creER TCR alpha fl/fl (or from control mice) into T cell deficient recipient mice. In this setting, Tregs from tamoxifen treated CD4-creER TCR alpha fl/fl mice were less potent in controlling naive T cell-induced inflammatory response.

Similarly, Tregs from tamoxifen treated CD4-creER TCR alpha fl/fl mice were less potent in controlling EAE induction in the recipient DEREG mice after MOG immunization.

In summary, this study and another one from Rudensky's lab published in Nature Immunology this month, indicate that while Foxp3 expression is essential for Treg identity, Tregs' functionality is a more complex trait and depends on continues stimulation through TCR signaling. 

What is puzzling for me is the fact that according to this study CD4-creER TCR alpha fl/fl mice retain ~30% TCR+ Tregs after tamoxifen injection and still show loss of overall Treg potency upon adoptive transfer. There are data to suggest that adoptive transfer of a single CD8 T cell can protect recipient mice from infection. Why are millions of supposedly normally functioning Tregs so inefficient?  

David Usharauli