Journal article
Antigen affinity, costimulation, and cytokine inputs sum linearly to amplify T cell expansion
JM Marchingo, A Kan, RM Sutherland, KR Duffy, CJ Wellard, GT Belz, AM Lew, MR Dowling, S Heinzel, PD Hodgkin
Science | Published : 2014
Abstract
Tcell responses are initiated by antigen and promoted by a range of costimulatory signals. Understanding how Tcells integrate alternative signal combinations and make decisions affecting immune response strength or tolerance poses a considerable theoretical challenge. Here, we report that Tcell receptor (TCR) and costimulatory signals imprint an early, cell-intrinsic, division fate,whereby cells effectively count through generations before returning automatically to a quiescent state. This autonomous program can be extended by cytokines. Signals from the TCR, costimulatory receptors, and cytokines add together using a linear division calculus, allowing the strength of a Tcell response to be ..
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Funding Acknowledgements
We thank S. Turner for providing the recombinant influenza virus and discussion and comments on the manuscript; L. Corcoran and V. Bryant for discussion and comments on the manuscript; A. Giang for discussion of experiments; M. Camilleri, L. Mackiewicz, M. Dayton, and D. Pavlyshyn for technical assistance; and P. Bouillet for Bcl2l11<SUP>-/-</SUP> mice. Fucci Red and Fucci Green mice were provided by the Riken BioResource Centre through the National BioResource Project of the Ministry of Education, Culture, Sports, Science, and Technology of Japan. We also thank K. Lafferty and his two-signal theory for inspiring this work. The data are tabulated in the main paper and in the supplementary materials. Experimental data and the code for fitting the Cyton model will be made available upon request. This work was supported by the National Health and Medical Research Council (NHMRC) through project grants 1010654 and 1043414, program grants 1054925 and 1037321, and fellowships to M. R. D., A. M. L., and P. D. H., K. R. D. and P. D. H. were supported by Human Frontier Science Program grant RGP0060/2012, G. T. B. was supported by an Australian Research Council Future Fellowship, and K. R. D. was supported by Science Foundation Ireland grant 12IP1263. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC Independent Research Institutes Infrastructure Support Scheme. J.M.M. was the recipient of an Australian Postgraduate Award and a Walter and Eliza Hall Institute Edith Moffat Scholarship.