One, No One, and One Hundred Thousand: T Regulatory Cells' Multiple Identities in Neuroimmunity

Abstract

As the Nobel laureate Luigi Pirandello wrote in his novels, identities can be evanescent. Although a quarter of a century has passed since regulatory T cells (Treg) were first described, new studies continue to reveal surprising and contradictory features of this lymphocyte subset. Treg cells are the core of the immunological workforce engaged in the restraint of autoimmune or inflammatory reactions, and their characterization has revealed substantial heterogeneity and complexity in the phenotype and gene expression profiles, proving them to be a most versatile and adaptive cell type, as exemplified by their plasticity in fine-tuning immune responses. Defects in Treg function are associated with several autoimmune diseases, including multiple sclerosis, which is caused by an inappropriate immune reaction toward brain components; conversely, the beneficial effects of immunomodulating therapies on disease progression have been shown to partly act upon the biology of these cells. Both in animals and in humans the pool of circulating Treg cells is a mixture of natural (nTregs) and peripherally-induced Treg (pTregs). Particularly in humans, circulating Treg cells can be phenotypically subdivided into different subpopulations, which so far are not well-characterized, particularly in the context of autoimmunity. Recently, Treg cells have been rediscovered as mediators of tissue healing, and have also shown to be involved in organ homeostasis. Moreover, stability of the Treg lineage has recently been addressed by several conflicting reports, and immune-suppressive abilities of these cells have been shown to be dynamically regulated, particularly in inflammatory conditions, adding further levels of complexity to the study of this cell subset. Finally, Treg cells exert their suppressive function through different mechanisms, some of which-such as their ectoenzymatic activity-are particularly relevant in CNS autoimmunity. Here, we will review the phenotypically and functionally discernible Treg cell subpopulations in health and in multiple sclerosis, touching also upon the effects on this cell type of immunomodulatory drugs used for the treatment of this disease.

Keywords: FoxP3; Treg heterogeneity; Treg-regulatory T cell; immune regulation; multiple sclerosis; neuroimmunity.

Figure 1

Treg cell plasticity. Treg cells have the potential to acquire expression of the molecular machinery which enables them to adapt to different environments, shadowing effector T cells and tissue-resident cells. This potential is schematically illustrated by the different colors, each corresponding to distinct cellular localization. Arrows indicate the known pathways of functional differentiation of Tregs and the tissues and organs where they can localize.

Figure 2

The microbiota shapes immune responses. The balance between proinflammatory and immune suppressive factors (dysbiosis, vit. D, stress, obesity, smoking, infections, diet) is critical for the maintenance of tolerance and avoidance of autoimmunity. Several environmental factors can influence this balance, with a main role being played by the gut microbiota.

Figure 3

Tregs in multiple sclerosis. Genetic and/or environmental factors may induce hordes of proinflammatory cells and thus may overcome the ability of Treg cells to suppress inflammation. This may unleash autoreactive immune cells which cross the blood brain barrier and target different areas of the CNS ultimately determining the development of white and gray matter lesions.