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

Guillaume Voisinne (1, 2, 3) , Briana G Nixon (4) , Anna Melbinger (5) , Georg Gasteiger (4, 6) , Massimo Vergassola (5) , Grégoire Altan-Bonnet (2, 3, 4)

1 CIML - Centre d'Immunologie de Marseille - Luminy
2 Center for Cancer Systems Biology
3 Memorial Sloane Kettering Cancer Center [New York]
4 Program in Immunology
5 Department of Physics
6 Institute of Medical Microbiology and Hygiene

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.

Mots clés: EFFECTOR; IL-2; ACTIVATION; MEMORY; AFFINITY; TCR; DIFFERENTIATION; PROLIFERATION; RECOGNITION; LYMPHOCYTES

Domaines: Biologie cellulaire

Guillaume Voisinne, Briana G Nixon, Anna Melbinger, Georg Gasteiger, Massimo Vergassola, et al.. T Cells Integrate Local and Global Cues to Discriminate between Structurally Similar Antigens. Cell Reports, 2015, ⟨10.1016/j.celrep.2015.04.051⟩. ⟨hal-01208299⟩