FOXP3+ Tregs play a major role in tolerance maintenance in the periphery. Most of FOXP3+ Tregs are thymus derived. Thymus is a specialized lymphoid tissue that generates novel T cells from their bone marrow precursors. The question whether naive T cells could convert into FOXP3+ Tregs in the periphery has not been settled.
It is believed that a "steady-state" condition favors FOXP3+ Tregs conversion in the periphery. However, a concept of "steady-state" is an arbitrary one, defined as absence of deliberate immunization or experimentally observed infection. In fact, whether "steady-state" truly exist is an open question as well.
Why this matters? Almost everyone agrees that in absence of so called "steady-state" naive T cells would convert into effector T cells rather than into FOXP3+ Tregs following antigen recognition. For example, if one wants to generate new FOXP3+ Tregs specific for particular antigen to treat autoimmune diseases, this task would be almost impossible to achieve if condition of "steady-state" does not actually exist in the body [from T cells' "point of view"].
Also, what cell types are responsible for that supposed FOXP3+ Tregs conversion? A new study in Immunity clarified this question somewhat. It showed that even in "steady-state" condition only minor subset of DCs within CD11c+ population defined by DEC205/CD8 expression were responsible for FOXP3+ Tregs "conversion" in T cell-replete mice [which harbor endogenous FOXP3+ Tregs].
For this study, the authors have used chimeric anti-DEC205 Ab [or anti-CD11c chimeric Ab as a control] that incorporate antigen of interest [MOG or OVA]. When injected into mice chimeric anti-DEC205 Ab, but not control, could "convert" naive MOG or OVA-specific T cells into FOXP3+ Tregs.
It appeared that DEC205+ CD11c+ DCs were also primarily BTLA+ and its expression were required for FOXP3+ Tregs induction.
Interestingly, the authors proposed that BTLA to HVEM signaling in naive T cells up-regulated CD5 and permitted FOXP3+ Tregs conversion even in presence of inflammatory cytokines such as IL-4 and IL-6.
However, in my view, such mechanism of FOXP3+ Tregs conversion even in presence of inflammation sounds counter-intuitive. Wouldn't it also induce FOXP3+ Tregs conversion from naive T cells specific for nonself antigen derived from pathogens during inflammation? Otherwise, how can system make sure that only self antigens are presented by DEC205+ DCs? The authors could only admit that this tolerance mechanism somehow only affects "self and tolerizing antigens". Also, what about endogenous FOXP3+ Tregs in these mice? Is it possible that endogenous thymus FOXP3+ Tregs are involved in assisting in FOXP3+ Tregs conversion, rather than DEC205+ DCs doing it alone from scratch? If so, implications are very different.