Figure 5.

Values of the decay rate of CTLA-4, d_{CTLA 4}, as a function of the stimulation time, τ _stim = t_{CD 8086} = t_MHC/A , associated to states of no activation (yellow), sustained activation (blue), or regulated activation (pink). For τ _stim < 7 units no activation arises; sustained activation ensues for 7 ≤ τ _stim ≤ 10, and regulated activation for τ _stim > 10. The first stage implies that a minimum stimulation time is necessary to boost activation; the second one, that CTLA-4 requires a minimal time of activation to be induced and perform inhibition; the third stage reveals that regulated activation only arises at later stimulation times and when the CTLA-4 decay rate is low, that is, d_{CTLA 4} < 1. Therefore, CTLA-4 should be induced for a time long enough to overcome a threshold level and its activity should be maintained to perform inhibition. The oscillatory behavior of the regulation threshold is associated to the inhibitory action of CTLA-4 which depends in turn on TCR and CD28 activation. This induces a stimulation-inhibition cycle which is downstream-propagated throughout the network. Consequently, the threshold d_{CT LA4} leading to regulation is determined by the expression level attained by activation inducers at a given phase of this cycle.