Dynamics of Peripheral Regulatory and Effector T Cells Competing for Antigen Presenting Cells
A healthy immune system requires a balance between effector T (T E ) cells that mount immune responses, and regulatory T (T R ) cells that prevent them. Understanding this balance requires knowing how the repertoires of T E and T R cells in the periphery are patterned and related to each other. The present work addresses this issue in the framework of the Crossregulation model, which was formulated to contemplate the dynamics of a large number of T cell clones recognizing a non-exclusive set of antigen-presenting cells (APCs). Assuming a continuous thymic export, three distinct patterns for the peripheral repertoire emerge from the simulations. These patterns are distinguished by the composition of the resident population, i.e., the subset of clones that can persist in the periphery. On one extreme, there is a repertoire pattern characterised by a predominance of T E cell clones and a too small T R -cell pool only maintained in the periphery by the continuous thymus export. Thus, this repertoire pattern cannot be the basis of a healthy immune system, because peripheral tolerance to self antigens is not ensured. On the other extreme, there is a repertoire pattern showing a predominance of T R cells maintained by their T E counterparts coming from the thymus. In spite of ensuring peripheral tolerance, this repertoire pattern does not appear efficient to fight infections occurring throughout life. In the middle of these two extremes lies a third repertoire pattern exhibiting a partition of the peripheral compartment similar to the one suggested in a previous work. In this repertoire structure, a small subset of highly crossreactive T R -cell clones prevents expansion of T E -cell clones driven by body antigens, and a more diverse subset of T E -cell clones remains uncontrolled by T R cells, which allows the setup of immune responses against harmful pathogens. This repertoire pattern seems then the most adequate to represent a healthy immune system. For each emergent repertoire pattern, clear and testable predictions are given for different properties related to the diversity of T E and T R cells. For the most adequate repertoire pattern, a higher diversity of T E cells than of T R cells is expected as** well as a negative correlation between clonal size distributions for clones belonging to the overlapping repertoire. These predictions can then be compared to available data on T cell receptor diversity.
KeywordsResi Stein Spondylitis Verse Santen
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This work was supported by Fundação para a Ciência e a Tecnologia (grants PTDC/SAU-MII/71402/2006) and a fellowship to NS (SFRH/BD/19810/2004). The authors would like to thank Prof. Ramit Mehr (Bar-Ilan University) for many comments on an early version of this paper.
- 3.Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, Kuniyasu Y, Nomura T, Toda M, Takahashi T (2001) Immunologic tolerance maintained by CD25 + CD4 + regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 182:18–32PubMedCrossRefGoogle Scholar
- 11.Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155: 1151–1164Google Scholar
- 32.Sepúlveda N (2009) How is the T-cell repertoire shaped? PhD thesis, University of PortoGoogle Scholar
- 47.Alper CA, Husain Z, Larsen CE, Dubey DP, Stein R, Day C, Baker A, Beyan H, Hawa M, Ola TO, Leslie RD (2006) Incomplete penetrance of susceptibility genes for MHC-determined immunoglobulin deficiencies in monozygotic twins discordant for type diabetes. J Autoimmun 27:89–95PubMedCrossRefGoogle Scholar
- 53.Sepúlveda N, Paulino CD, Carneiro J (2008) Diversity of regulatory and effector T lymphocytes (in portuguese). In: Hill MM, Ferreira MA, Dias JG, Salgueiro MF, Carvalho H, Vicente P, Braumann CA (eds) Estatística: da Teoria à Prática. SPE editions, pp 513–523Google Scholar