T cells translate individual, quantal activation into collective, analog cytokine responses via time-integrated feedbacks

• Main Authors: Karen E Tkach, Debashis Barik, Guillaume Voisinne, Nicole Malandro, Matthew M Hathorn, Jesse W Cotari, Robert Vogel, Taha Merghoub, Jedd Wolchok, Oleg Krichevsky, Grégoire Altan-Bonnet
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2014-04-01
• Series: eLife
• Subjects: systems immunology; T lymphocyte activation; cytokine; self-organization; feedback regulation; immune monitoring
• Online Access: https://elifesciences.org/articles/01944

Variability within isogenic T cell populations yields heterogeneous ‘local’ signaling responses to shared antigenic stimuli, but responding clones may communicate ‘global’ antigen load through paracrine messengers, such as cytokines. Such coordination of individual cell responses within multicellular populations is critical for accurate collective reactions to shared environmental cues. However, cytokine production may saturate as a function of antigen input, or be dominated by the precursor frequency of antigen-specific T cells. Surprisingly, we found that T cells scale their collective output of IL-2 to total antigen input over a large dynamic range, independently of population size. Through experimental quantitation and computational modeling, we demonstrate that this scaling is enforced by an inhibitory cross-talk between antigen and IL-2 signaling, and a nonlinear acceleration of IL-2 secretion per cell. Our study reveals how time-integration of these regulatory loops within individual cell signaling generates scaled collective responses and can be leveraged for immune monitoring.