Type I IFNs produced during viral infection promotes bystander regulatory T cells

Foxp3⁺ regulatory T cells are one of my favorite topics. Foxp3⁺ T cells are the most powerful regulatory subset within immune system. It is unbelievable but true that as of today only sure thing we know about Foxp3⁺ T cells is the fact that their absence or ablation leads to severe and total autoimmune organ disorders and death. No other T or B cells or innate subsets produce such a dramatic effect on the body.

At the same time, we are still have no clear answer whether Foxp3⁺ regulatory T cells operate in an antigen-specific manner or whether they non-specifically suppress "overly" excessive immune response (both innate or adaptive driven).

There are several hypothetical questions regarding Foxp3⁺ T cells that would require experimental proof before we can make any significant breakthrough. 

For example, 

"if Foxp3⁺ T cells are so potent, how immune response is initiated in the first place?" 

"If initial inflammatory stimuli temporary inactivates Foxp3⁺ T cells to allow initiation of immune response, how long such inactivation lasts?" 

"if Foxp3⁺ T cells regulate excessive immune response (excessive inflammation), how they can sense what is excessive?"

In this regard new paper in Nature Immunology from Steven Ziegler's lab is interesting to read. Here, the authors showed that pre-exposure of naive antigen-inexperienced CD4 T cell to type I IFNs initiates their differentiation towards regulatory pathway rather than effector. Such scenario possibly prevents excessive bystander activation of naive T cells and reduces overall tissue damage.

In vitro studies showed that CD4 T cells initially pre-exposed in vivo to polyI:C (as a source of type I IFN) and then co-cultured with antigen-pulsed DCs and TGF-β tended to preferentially develop into Foxp3⁺ T cells.

Such preference for Foxp3⁺ T cell development were abolished with CD4 T cells from IFNαR1^KO mice.

RIP-mOva × Rag2KO hosts receiving naive OVA-specific T cells pre-exposed to polyI:C do not develop diabetes (c), while RIP-mOva × Rag2KO hosts receiving control naive OVA-specific T cells together with polyI:C rapidly developed diabetes. Importantly, secondary exposure to polyI:C of RIP-mOva × Rag2KO hosts transferred with naive OVA-specific T cells pre-exposed to polyI:C still did not break tolerance (d).

These experiments indicated that simultaneous exposure of naive T cells to antigen and type I IFNs drove effector differentiation, but if they were first pre-exposed to type I IFNs and then to antigens it drove their Foxp3⁺ T cell differentiation. Indeed, this observations were confirmed in subsequent experiments that revealed that exposure to type I IFNs 2-3 days before antigenic exposure provided the most optimal condition for Foxp3⁺ T cell development.

In summary, this study suggests the following scenario: type I IFNs released during viral infection conditioned bystander, nonspecific naive T cells for Foxp3⁺ T cell development. This mechanism potentially prevents excessive activation and effector differentiation of naive T cells encountering antigens later during immune response (including tissue-derived self-antigens).

David Usharauli