Tuning One's Sense of Self: How T Cells' Signaling Network Discriminate Dynamically Between Self and Non-Self in the Immune System

Grégoire Altan-Bonnet

Computer Biology & Immunology, Memorial Sloan-Kettering Cancer Center

To fight viral or bacterial infections effectively without endangering their own viability, vertebrate organisms rely on the ability of their adaptive immune system to distinguish self- from non-self agents. Among the many components of the adaptive immune system, the major CD4+ and CD8+ subsets of T cells recognize antigens from these infectious organisms using their somatically-mutated receptor (TCR). We combined computational modeling and experimental measurements, to understand how the dynamics of two competing feedback loops activated by TCR engagement play major roles in ligand discrimination by T cells. These signaling feedback loops control a high gain digital amplifier that sets a threshold in terms of the quality of ligand-receptor interaction effective in activating the T cell. Together with the filtering effect of thymic selection on the self-specific repertoire, this contributes to useful self/non-self discrimination. We will present the main components of our TCR signaling model accounting for its ligand discrimination as well as predictions that the threshold for such discrimination could be modulated during differentiation by modest alterations in the intracellular concentration of key signaling proteins, an effect that could have important implications for a positive role of self-recognition in anti-foreign immune responses.