A logical analysis of T cell activation and anergy

Abstract

Interaction of the antigen-specific receptor of T lymphocytes with its antigenic ligand can lead either to cell activation or to a state of profound unresponsiveness (anergy). Although subtle changes in the nature of the ligand or of the antigen-presenting cell have been shown to affect the outcome of T cell receptor ligation, the mechanism by which the same receptor can induce alternative cellular responses is not completely understood. A model for explaining both positive (cell proliferation and cytokine production) and negative (anergy induction) signaling of T lymphocytes is described herein. This model relies on the autophosphorylative properties of the tyrosine kinases associated with the T cell receptor. One of its basic assumptions is that the kinase activity of these receptor-associated enzymes remains above background level after ligand removal and is responsible for cellular unresponsiveness. Using a simple Boolean formalism, we show how the timing of the binding and intracellular signal-transduction events can affect the properties of receptor signaling and determine the type of cellular response. The present approach integrates into a common framework a large body of experimental observations and allows specification of conditions leading to cellular activation or to anergy.

Figure 1

Schematic interaction diagram. f = free ligand; b = TCRs bound to ligand; k = receptor-associated PTK activity; x = tyrosine kinase-dependent inhibitory pathway; s = metabolic and mitogenic response. Positive and negative interactions are indicated by a plus and minus sign, respectively.

Figure 2

Transition diagram showing the sequences of states and possible pathways. The total time to reach a given state, relative to time 0, is written next to each state in terms of the characteristic transition times (delays) of the state variables. An asterisk (∗) indicates the stages corresponding to cellular activation (s = 1).

Figure 3

(a) Secondary response. Addition of free ligand to the anergic state fails to evoke a productive response (see Eq. 5 for ligand rebinding). After ligand dissociation and removal the system returns to the unresponsive state. (b) Reversal of anergy. Addition of the signaling component s to the anergic state restores the fully responsive state.