Pathogen-sensing and regulatory T cells: integrated regulators of immune responses.

We present the concept that pathogen-sensing and regulatory T cells (Treg) mutually regulate immune responses to conventional and tumor antigens through countervailing effects on dendritic cells (DC). Normally, conventional CD4 T cells recognizing their cognate antigen presented by a DC will respond only if the DC also receives a signal through its pathogen-sensing/danger/adjuvant recognition systems (the pathogen-sensing triad). However, in the absence of Tregs capable of interacting with the same DC, DCs are competent to present antigens, both foreign and self, even without the stimulation provided by the pathogen-sensing triad. Tregs recognizing an antigen presented by the DC that is also presenting antigen to a conventional CD4 T cell will prevent the activation of the CD4 T-cell responses, but a signal delivered by a member of the pathogen-sensing triad will overcome the inhibitory action of Tregs, thus allowing CD4 T-cell responses to go forward. These considerations take on special meaning for responses to "weak antigens" such as many of the antigens displayed by spontaneous human tumors. ©2014 American Association for Cancer Research.