Potentially autoreactive T cells are controlled by both cell-intrinsic and dominant trans-suppressive mechanisms. One of the major mediators of dominant suppression of immune responses are regulatory CD4+ T cells that express the transcription factor Foxp3. These cells can arise during thymic T cell development or be induced in the periphery from naïve CD4+ T cells. The factors that drive development of induced regulatory T cells can represent a critical choice for health or autoimmunity in the case of potentially self-reactive CD4 T cells. Numerous studies have implicated a role for enhanced effector differentiation and suppressed induction of regulatory T cells in response to antigen in the context of inflammatory signals. Here we show that inflammatory stimuli can drive expansion of functional Foxp3+ regulatory T cells in vivo, largely driven by type I interferon signals. Furthermore, naïve CD4+ T cells that are bystander-activated by interferon in the absence of cognate antigen exhibit tolerance, reduced effector function, and enhanced induction of Foxp3 upon subsequent antigen encounter. These data suggest that transient bystander activation imposes a dynamic state of responsiveness in naïve CD4+ T cells, in which the nature of subsequent differentiation is shaped by temporal coordination of antigen/TCR and inflammatory signals. This work provides an interesting new framework for potential antigen-specific therapeutic immunization strategies.
- Copyright © 2013 by The American Association of Immunologists, Inc.