Antigen affinity, costimulation, and cytokine inputs sum linearly to amplify T cell expansion

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Science  28 Nov 2014:
Vol. 346, Issue 6213, pp. 1123-1127
DOI: 10.1126/science.1260044

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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.

Stimulatory signals add up for T cells

T cell activation is a dynamic process. T cells encounter multiple input signals such as antigens, costimulatory molecules, and cytokines at different times and anatomical locations during an infection. But how do T cells integrate this information to determine the extent to which they divide? To find out, Marchingo et al. stimulated mouse T cells in culture with different combinations of inputs and also tracked antigen-specific T cell responses in mice infected with influenza virus. They found that T cells linearly sum the various stimulatory inputs they receive to determine their “division destiny.”

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