In the “triggering phase,” T lymphocytes activated by exposure to the antigen release IFN-γ that, possibly in conjunction with a not yet identified membrane signal, activates inflammatory monocyte precursors. Whereas in resting condition this would result in induction of classically activated macrophages, monocytes conditioned by tumors show a different program because of the expression of IL-4Rα and the ability to release both IL-13 and IFN-γ. The IFN-γ production, initially sustained by activated T lymphocytes, is subsequently amplified by the cytokine released from activated monocytes. IFN-γ allows the prolonged expression and signaling of IL-4Rα after engagement by IL-13 released via an autocrine circuit. During the “amplification phase,” the cytokines are thus able to maintain a prolonged activation of the enzymes NOS and ARG, which ultimately originate the immunosuppressive mediators acting on the CD8⁺ T cells. This model supports the view that a prolonged stimulation of MSCs is necessary to mediate a full inhibition of CD8⁺ T cells and explains why T cells can initially proliferate in the presence of spleen-derived MSCs. On the other hand, ARG and NOS are constitutively activated in tumor-infiltrating MSCs, which account for the prompt immunosuppression provided by these cells (Figure 1).