Dynamics of Peripheral Regulatory and Effector T Cells Competing for Antigen Presenting Cells

Abstract

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 J. Carneiro ( )

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome as a Hyper-Regulated Immune System Driven by an Interplay Between Regulatory T Cells and Chronic Human Herpesvirus Infections

“…Given the high combinatorial nature of the genetic rearrangement mechanism encoding the T-cell receptor, these new clones should exhibit different antigen specificities from the ones already existing in the periphery. Interestingly, early work using a more complex cross-regulation model demonstrated that most of the clonal selection shaping the T-cell repertoire occurs early in life (21). After this time period, the resulting T-cell repertoire is enriched with resident clones at sufficiently high density.…”

“…Independence between clones in the repertoire simplifies the analysis as one only needs to interpret all possible dynamics of a single clone associated with a given set of cAPC. This implies that Tregs and Teffs from the same clone cross-regulate each other, but the same cells from different clones do not; a model assuming a cross-regulation between distinct clones can be found elsewhere (21).…”