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

•Strongly activated T cell clones induce weaker clones to proliferate through IL-2•IL-2-induced PI3K activation mediates the co-optation of weak T cell clones•A quantitative model shows how antigen and IL-2 signal additively to activate T cells•Co-optation is set by cell number, antigen load, and competition with T-reg cells

SummaryT 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.

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