Molecular and functional heterogeneity of T regulatory cells

Lequn Li, Vassiliki A Boussiotis, Lequn Li, Vassiliki A Boussiotis

Abstract

Naturally occurring CD4+ T regulatory (Treg) cells are produced during maturation in the thymus and have a mandatory role in maintaining homeostasis and immune quiescence. Development and function of Treg cells depends on the transcription factor forkhead box P3 (Foxp3), which is necessary and sufficient for Treg cell function. Currently emerging evidence indicates Treg cells display molecular and functional heterogeneity and can be categorized into naïve and effector- or memory-like cells, which can produce effector cytokines supporting the idea that Treg cells retain plasticity. The role of Treg cells that acquire these properties remains unclear and is currently under intense investigation. In this review, we summarize recent advances on the differentiation of effector- or memory-like Treg cells, the impact of the cytokine milieu on the molecular and functional heterogeneity of Treg cells, and the clinical implications of the heterogeneity and specialization of Treg cells.

Copyright © 2011 Elsevier Inc. All rights reserved.

Figures

Figure 1. Post-thymic differentiation of T reg…
Figure 1. Post-thymic differentiation of Treg cells
The majority of Treg cells at birth are naïve cells and express high levels of CD62L, CCR7 and the gut homing receptor α4β7 allowing them to migrate into secondary lymphoid organs and gut-associated lymphoid tissues where naive Treg cells encounter self-antigens and commensal microbes. Subsequently, Treg cells express diverse homing receptors, which render them capable of migrating to specific tissues and organs. For instance, expression of CCR4 is required for migration to skin, lung and other inflamed tissues; T-bet-dependent expression of CXCR3 is important for localization of Treg cells to inflamed liver; Treg cells expressing CCR6 are able to migrate to Th17 cell-mediated inflammatory sites. Upon recognition of antigen Treg cells, like conventional naïve T cells, lose their naïve phenotype and become effector- or memory-like cells expressing distinct surface markers. Thus, post-thymic differentiation of Treg cells occurs through a sequence of events that involve antigen recognition, migration and functional maturation, which eventually determine the specific function and fate of Treg cells.
Figure 2. A model of functional specialization…
Figure 2. A model of functional specialization of Treg cells
The differentiation of naïve CD4+ T cells into distinct effector subsets, such as Th1-, Th2- and Th17- cells is controlled by key transcription factors that are induced by different environmental factors including the type of pathogen and cytokine milieu. It seems that Treg cells can also differentiate into distinct subsets that are capable of regulating responses of individual T effector cell populations. Thymus-derived Foxp3+ Treg cells differentiated in the presence of IFN-γ express T-bet and specifically suppress the function and expansion of Th1 cells. IRF4 deficient Treg cells are incapable of suppressing Th2 cells but retain their suppressive activity on Th1 and Th17 cells. Treg cells lacking Stat3 are unable to control Th17 cell-mediated inflammation. Although the driving forces regulating expression of IRF-4 and Stat3 in Treg cells have not yet been identified, it seems that Treg cells might use specific molecular programs controlled by transcription factors to restrain particular types of immune responses mediated by distinct effector T cell subsets.

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