Regulatory T Cells
How do regulatory CD25+ T cells and their targets talk to each other?
Jorge Carneiro, Instituto Gulbenkian de Ciencia, Portugal.
Regulatory CD25+ CD4+ T lymphocytes (regulatory cells for short) have been implicated in peripheral tolerance (reviewed by Sakaguchi (2000)), in the regulation of otherwise pathogenic consequences of immune responses to invading pathogens (Powrie, 1997; Read, 2000), and also in controlling the expansion of the remaining CD4 compartment (homeostasis) (Annacker, 2001). Despite their fundamental interest and their potential clinical applications, regulatory cells are still not very well understood. Regulatory T cells seem to prevent responses by other T cells (target cells) through an inhibitory interaction, whose nature is controversial. Alternative hypotheses range from interactions dependent on multicellular conjugates with APC (reviewed in León (2000)), to cytokine-mediated interactions (Asseman, 1999; Annacker, 2001), including interactions conveyed by APC (Taams, 2000; Cederbom, 2000) and direct TCR-non-specific contact between T cells (Thornton & Shevach, 2000). We have been trying to sort out these alternative hypotheses by analysing their quantitative predictions.
Figure 1: The key event or process when regulatory cells interact with their targets could be direct encounter between the two cells (top left), the production, diffusion and response to a cytokine (top right), an encounter between the two cells in multicellular conjugates with APC (bottom left) or sequential encounters of regulatory cell with the APC, modification of the APC and encounter of the modified APC with target cells (bottom right).
Our strategy consists in translating the different candidate mechanisms into mathematical models (the major classes under study are illustrated in fig. 1). To investigate and compare the properties of these models in formal grounds, aiming to identify their unique and distinguishing features. The properties identified in this way, are used to design appropriate experimental protocols that can discriminate which putative models (read mechanisms) can underlie the observations on regulatory cells, and which putative models can not. In a nutshell, we try to establish a taxonomic tree based on the quantitative properties predicted by the different candidate mechanisms. This tree can be used both in the design conclusive experimental tests, and to extract more information from already available data.
Figure 2: The models illustrated in the left are fittied to experimental inhibition index on the right. Because interactions in multicellular conjugates with APC have limited efficiency the data can only be explained if regulatory cells (gray) use target cells (white) as a growth factor.
Following this strategy, we have dismissed the hypothesis, proposed before by others, that regulatory cells suppress other cells by passive competition for conjugation with the APC (León et al. 2000, 2001). We have also shown that interactions among T cells involving the multicellular conjugates with the APC are a relatively inefficient mechanism, but that they are compatible with the body of evidence for regulatory T cells, but this is only true if regulatory cells would use their targets as a growth factor (León et al. 2000, 2001) (these results are illustrated in fig. 2). After this theoretical prediction, we have confirmed that regulatory cells may grow when co-cultured in vitro with their targets by following the proliferation of regulatory cells using CFSE.
This study of the mechanism of action of regulatory cells is an illustration of how an interdisciplinary approach to complex biological system may give better insights and, in some cases, allow overcoming some obstacles inherent to purely experimental approaches. In the context of the immunological monster metaphor, our approach appears as yet another perspective on the monster and another strategy to tackle it.
You can find more detailed information at the Website of this Group of "Hunters of the Immunological Monster".
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