Journal
SCIENCE
Volume 346, Issue 6213, Pages 1123-1127Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1260044
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Funding
- National Health and Medical Research Council (NHMRC) [1010654, 1043414, 1054925, 1037321]
- Human Frontier Science Program [RGP0060/2012]
- Australian Research Council Future Fellowship
- Science Foundation Ireland [12IP1263]
- Australian Postgraduate Award
- Walter and Eliza Hall Institute Edith Moffat Scholarship
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T cell responses are initiated by antigen and promoted by a range of costimulatory signals. Understanding how T cells integrate alternative signal combinations and make decisions affecting immune response strength or tolerance poses a considerable theoretical challenge. Here, we report that T cell 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 T cell response to be predicted from the sum of the underlying signal components. These data resolve a long-standing costimulation paradox and provide a quantitative paradigm for therapeutically manipulating immune response strength.
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