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 like antigen quality and quantity, to global ones like the extracellular concentration of inflammatory cytokines.
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