T Cells Integrate Local and Global Cues to Discriminate between Structurally Similar Antigens.

T lymphocytes’ ability to discriminate between structurally related antigens has been attributed to the unique signaling properties of the T cell receptor. However， recent studies have suggested that the output of this discrimination process is conditioned by environmental cues. Here， we demonstrate how the IL-2 cytokine， collectively generated by strongly activated T cell clones， can induce weaker T cell clones to proliferate. We identify the PI3K pathway as being critical for integrating the antigen and cytokine responses and for controlling cell-cycle entry. We build a hybrid stochastic/deterministic computational model that accounts for such signal synergism and demonstrates quantitatively how T cells tune their cell-cycle entry according to environmental cytokine cues. Our findings indicate that antigen discrimination by T cells is not solely an intrinsic cellular property but rather a product of integration of multiple cues， including local cues such as antigen quality and quantity， to global ones like the extracellular concentration of inflammatory cytokines.