Table 1.
Summary of mechanistic models of Treg action.
| Cell populations considered | Mechanisms of regulation of immune response | Some properties of the model | Reference |
|---|---|---|---|
| APC, Treg, Teff, and Treg, Teff conjugates on APC | Competition for activation on APC Tregs inhibit Teff on same conjugate Treg maintenance is dependent on Teff | Treg inhibit growth of Teff Treg induce Teff to become Treg | (92–94, 96) |
| No explicit APC dynamics | |||
| As above plus IL2 | Competition for IL2 | Non-local interactions | (97, 98) |
| Tregs condition APC | Model used to study IL2-based therapies | ||
| APC and Ag dynamics | Tregs directly suppress Teff (specifically and bystander) | Bystander effects are important | (99) |
| APC maturation | Tregs suppress APC maturation | Direct suppression was more effective | |
| T cells are activated into Treg or Teff by APC stimulation | |||
| Antigen | Tp become Treg by interaction with resting APC | Strength of antigen stimulus is crucial in defining whether system is in tolerant or non-tolerant state | (100) |
| Immature APC, resting APC, activated APC | Tp become Teff by interaction with activated APC Teff activates APC Treg induces activated APC to rest | ||
| Precursor T cells (Tp), Teff, Treg | |||
| Stochastic model of TCR triggering for T cells (both thymus and periphery) | Different thresholds for activation vs. anergy, with or without co-stimulation | Self-reactive cells in periphery are controlled by a mechanism of reversible anergy | (103) |
| T cells with tunable activation thresholds | Model for integration of signals in successive encounters with APC | Exhibits self-tolerance | (102) |
| “More cells should lead to less anergy,” which is not seen in adoptive transfer experiments | |||
| Inactive and active Treg and Teff | Tregs consume IL2 | Strength of antigen stimulation (for Treg and Teff) defines relative levels of those two populations | (107–109) |
| IL2 for Teff proliferation, also helps Treg proliferate | Treg inhibit Teff (from active to inactive) proportionally to Treg numbers | ||
| Cytokine (e.g., IL7) for Treg homeostasis | |||
| APC with different antigens Teff of multiple specificities Tregs of multiple specificities | Cells interact with extensive cross-reactivity, but different avidities | Effector functions are the outcome of individual cellular decisions (based on cross-reactivity) | (111) |
| A threshold of conjugation time can be identified that permits self/non-self discrimination |
Comparison of some of the models for Treg action discussed in the text. The model by Kim et al. (110) is too complex to fit in this summary table.