Model depicting TLR-mediated T- and NK-cell immunosuppression. (A) Persistent Ag-independent activation of NK cells and MSCs by single or multiple TLRLs, typical of pathogens (infections) or endogenous compounds (cancer and autoimmune diseases), leads to an inflammatory response characterized by the production of IFN-γ. This can occur in conjunction with Ag-dependent T cell activation, which also contributes to the increased concentrations of IFN-γ. (B) Elevated levels of IFN-γ, together with TLRL persistence, lead to the recruitment/expansion and activation of MSCs within the affected tissue and lymphatic organs. (C) The continuous presence of activated MSCs affects the surrounding T and NK cells, leading to their hyporesponsiveness and loss of ζ-chain expression, which is a biomarker “sensing” changes in the chronic inflammatory immunosuppressive environment.