Stochastic model of T cell proliferation: a calculus revealing IL-2 regulation of precursor frequencies, cell cycle time, and survival.

The outcome of Ag exposure is dictated by complex regulation of T cell proliferation. The rates of proliferation and survival are altered by numerous signals that the cell receives and integrates to achieve a net response. We have illustrated previously how small changes in kinetic parameters can lead to large differences, even under conditions of saturating IL-2.

T cell fitness determined by signal strength.

Two potential outcomes confront proliferating antigen-stimulated naive T cells: differentiation to effector and memory cells, or deletion. How stimulation affects cell fate is unclear. Autonomous CD8+ T cell differentiation has been proposed, but this does not explain the abortive proliferation of T cells induced by immature dendritic cells.

A cellular calculus for signal integration by T cells.

During an immune response numerous receptor-mediated signals delivered to T cells direct their proliferation, survival and differentiation. Here, we describe a quantitative model and in vitro methods for assessing the "calculus" used by T cells to process these multiple signals. The model reveals how T cells convert independently received signals into linear additive effects on division times which, in turn, amplify T cell number exponentially.

Quantitative analysis of lymphocyte differentiation and proliferation in vitro using carboxyfluorescein diacetate succinimidyl ester.

Mature T and B lymphocytes respond to receptor-delivered signals received during and following activation. These signals regulate the rates of cell death, growth, differentiation and migration that ultimately establish the behaviour patterns collectively referred to as immune regulation. We have been pursuing the philosophy that in vitro systems of lymphocyte stimulation, when analysed quantitatively, help reveal the logical attributes of lymphocyte behaviour.

The logic of intercellular communication in the immune system.

The collaboration between T and B lymphocytes is used as an example to illustrate how the key features of immune regulation (cell interaction, reciprocal exchange of signals by cell contact, and dependence on soluble cytokines) serve as amplifying reactions. By linking cell-based amplifiers in sequence, the resulting immune response is made highly sensitive to small changes in the environment. Thus, intercellular communication in the immune system can be viewed as a higher level analogue to the kinase cascades that amplify intracellular signalling mechanisms.