T cells translate individual, quantal activation into collective, analog cytokine responses via time-integrated feedbacks.
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. DOI: http://dx.doi.org/10.7554/eLife.01944.001.
Program in Computational Biology and Immunology, Memorial Sloan Kettering Cancer Center, New York, United States.
Karen E
KE
Tkach
Debashis
D
Barik
Guillaume
G
Voisinne
Nicole
N
Malandro
Matthew M
MM
Hathorn
Jesse W
JW
Cotari
Robert
R
Vogel
Taha
T
Merghoub
Jedd
J
Wolchok
Oleg
O
Krichevsky
Grégoire
G
Altan-Bonnet
D000818:Animals; D000941:Antigens / Q000276:immunology / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication; D002478:Cells, Cultured; D018920:Coculture Techniques; D003198:Computer Simulation; D025461:Feedback, Physiological; D005838:Genotype; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism*; D007700:Kinetics; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018448:Models, Immunological; D017711:Nonlinear Dynamics; D010641:Phenotype; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*
D000941:Antigens; D000951:Antigens, Neoplasm; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D050799:STAT5 Transcription Factor
T lymphocyte activation; cytokine; feedback regulation; immune monitoring; self-organization; systems immunology