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Th1/Th2 cross regulation
1Theoretical Biology and Biophysics, Theoretical Division, Los Alamos National Laboratory, NM 87545.
Insights
Immune responses are dominated by either Th1 or Th2 cells, not both, due to regulatory cytokines. Perturbations can switch responses, impacting infections and potentially guiding vaccine design.
Area of Science:
- Immunology
- Computational Biology
- Systems Biology
Background:
- The immune system utilizes distinct helper T cell subsets, Th1 and Th2, which have opposing regulatory roles.
- Cytokines like interferon-gamma (IFN-γ) and interleukin-10 (IL-10) mediate cross-regulation between Th1 and Th2 cells.
- Understanding this cross-regulation is crucial for comprehending immune responses to various pathogens and self-antigens.
Purpose of the Study:
- To present and analyze a mathematical model of Th1/Th2 cell cross-regulation mediated by IFN-γ and IL-10.
- To investigate the factors determining the dominance of Th1 or Th2 responses.
- To explore the implications of this regulatory network for parasitic infections, HIV, autoimmunity, and tumor immunity.
Main Methods:
- Development of a computational model simulating the interactions between Th1 and Th2 cells and their regulatory cytokines.
- Analysis of model dynamics to predict the conditions favoring Th1 or Th2 dominance.
- Comparison of model predictions with existing experimental data and observations.
Main Results:
- The model predicts that immune responses are typically dominated by either Th1 or Th2 cells, with dominance determined by relative activation efficiencies.
- The system can be perturbed to switch from a Th2 to a Th1 response, or vice versa.
- The model accounts for outcomes in parasitic infections (e.g., Leishmania major) and suggests potential applications in HIV vaccine design and tumor immunity.
Conclusions:
- Th1/Th2 cross-regulation by IFN-γ and IL-10 leads to polarized immune responses.
- The model provides insights into immune evasion strategies, such as the 'sneaking through' phenomenon in tumor immunity.
- Findings support the potential for novel vaccination strategies, including using low doses of live parasites for protection and informing AIDS vaccine development.
Abstract:
We present and analyze a model for the cross-regulation of the Th1 and Th2 helper cell subsets during an immune response by the regulatory cytokines interferon-gamma (IFN)-gamma) and interleukin-10 (IL-10). IFN-gamma, secreted by Th1 cells, can inhibit the proliferation of Th2 cells. Interleukin-10, secreted by Th2 cells, inhibits cytokine production by Th1 cells. Based on these properties, the model shows that responses are expected to be dominated by either Th1 cells or Th2 cells but not both. Which type dominates is shown to depend principally on the relative efficiencies of activation of the responding Th1 and Th2 cells. However, our model, as well as numerous experiments, show that perturbations of the system allow one to switch from a Th2 to a Th1 response, or vice versa. Our model can account for observed outcomes of parasitic infection and may also contribute to our understanding of immune responses to HIV infection as well as to tolerance to self components. It also predicts that in certain parameter ranges vaccination with low doses of live parasites can provide protection against subsequent encounters with high doses that normally induce disease. Experiments by Bretscher et al. (1992, Science 257, 539) on Leishmania major infection are consistent with this prediction. A similar strategy may also be relevant for the design of an AIDS vaccine. Lastly, our results indicate that Th1/Th2 cross-regulation is capable of generating a "sneaking through" phenomenon, and hence it may play a role in tumor immunity.