T-cell responses are initiated by antigen and promoted by a range of cell-contact associated and secreted costimulatory molecules. Regulation of T-cell response kinetics by manipulating the strength and availability of T cell stimuli represents an important emerging therapeutic strategy in the treatment of cancer and allograft rejection. Nevertheless, how T cells integrate alternative signal combinations to make decisions affecting tolerance and response strength still poses a significant theoretical challenge.
Here we show that T cell receptor and cell-contact associated costimulatory signals imprint an early, cell-intrinsic, division fate whereby cells effectively count through generations before returning automatically to a quiescent non-dividing state. This autonomous program can be extended by cytokines, with IL-2 adding up to ten generations before T cells return to quiescence when maintained at high levels. Signals from multiple costimulatory molecules and cytokines sum together using a linear division calculus that leads to geometric increases in peak population expansion with each additional input. As a consequence we find the strength of a T-cell response can be predicted from the sum of the underlying signal components.
These findings provide a quantitative framework relating integration of T cell signal combinations with kinetic outcomes, in particular the magnitude of T-cell expansion. Importantly, with further development, this quantitative framework has the potential to facilitate the optimisation of costimulation based therapies used to modulate the immune response during cancer and allograft transplantation.