title: T Cells Integrate Local and Global Cues to  Discriminate between Structurally Similar Antigens.
abstract: 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.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Voisinne
authors.forename: Briana G
authors.initials: BG
authors.lastname: Nixon
authors.forename: Anna
authors.initials: A
authors.lastname: Melbinger
authors.forename: Georg
authors.initials: G
authors.lastname: Gasteiger
authors.forename: Massimo
authors.initials: M
authors.lastname: Vergassola
authors.forename: Grégoire
authors.initials: G
authors.lastname: Altan-Bonnet
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000941:Antigens; D016207:Cytokines; D007376:Interleukin-2; D019869:Phosphatidylinositol 3-Kinases