Pathogen-sensing, regulatory T cells, and responsiveness-tuning collectively regulate foreign- and self-antigen mediated T-cell responses.

The concept that induction of T-cell-dependent immune responses requires both T-cell recognition of an epitope and recognition by the innate immune system of pathogen-associated molecular patterns needs to be extended to include the contribution of regulatory T cells and of responsiveness-tuning. Here we develop the hypothesis that both pathogen sensing and regulatory T cells act on antigen-presenting dendritic cells (DCs) to determine whether the DCs will be competent to activate T cells with cognate receptors. Tregs that recognize self-peptide/major histocompatibility complexes (MHCs) on the DC in question will serve to inactivate that DC, whereas sensing of pathogens or innate "danger" signals by the DC will oppose the action of the Tregs. The responsiveness of the T-cell compartment is further controlled by activation-threshold tuning in which responsiveness is adjusted to the strength of recurrent stimulation of T cells by self-peptide/MHCs in the periphery. Thus, a robust T-cell response depends on T-cell recognition of a peptide/MHC presented by a competent DC, competence depending on interactions with Tregs and the degree of innate stimulation through pathogen sensing, and on a combined TCR and accessory-signaling strength of stimulation that exceeds the activation threshold of the T cells, determined by its responsiveness tuning.