Hypothesis: loss of telomerase inducibility and subsequent replicative senescence in cultured human T cells is a result of altered costimulation

Telomerase activity is upregulated after stimulation of human T cells, but as they progress through their finite culture lifespans, this ability is progressively lost. Upregulation of telomerase requires T cell stimulation through the antigen receptor (TCR) and through costimulatory receptors such as CD28. A hypothesis is put forward here that T cell signalling through the TCR is maintained throughout the lifespan of the clones, and that alterations in costimulatory signals are responsible for the progressive loss of telomerase induction. A minimal model of T cell activation during progression through the lifespan is presented in which the TCR provides an unchanging signal 1, but in which there is a progressive decrease in CD28 signalling (signal 2), as well as a decrease in other costimuli, which are here designated as signal 4 (via CD134) and 5 (via CD154). Moreover, in addition, increases in negative costimulation, here designated signal minus 2 (via CD152) and possibly via ICOS (signal 3) may play a part. The balance of these positive and negative signals at each encounter with antigen will determine T cell fate by regulating activation and telomerase induction.