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Clin Exp Immunol. 2019 Mar 12. doi: 10.1111/cei.13290. [Epub ahead of print]

Mechanisms of human Foxp3+ Treg cell development and function in health and disease.

Author information

1
Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada, H3A 2B4.
2
Program in Infectious Diseases and Immunology in Global Health, the Research Institute of the McGill University Health Centre, Montréal, Québec, Canada, H4A 3J1.
3
Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada, H4A 3J1.

Abstract

Regulatory T (Treg ) cells represent an essential component of peripheral tolerance. Given their potently immunosuppressive functions orchestrated by the lineage-defining transcription factor Foxp3, clinical modulation of these cells in autoimmunity and cancer is a promising therapeutic target. However, recent evidence in mice and humans indicates that Treg cells represent a phenotypically and functionally heterogeneic immune cell population. Indeed, both suppressive and non-suppressive Treg cells exist in human blood that are otherwise indistinguishable from one another using classical Treg cell markers like CD25 and Foxp3. Moreover, work in mice demonstrated that Treg cells display a degree of plasticity that is essential for optimal suppression through which they acquire the trafficking pathways needed to home to tissues containing target effector T (Teff ) cells. However, this plasticity could also result in Treg cell lineage instability and acquisition of pro-inflammatory Teff cell functions. Consequently, these dysfunctional CD4+ Foxp3+ cells may fail to maintain peripheral tolerance and instead support immunopathology. Mechanisms driving human Treg cell dysfunction are largely undefined, and obscured by the scarcity of reliable immunophenotypic markers and the disregard paid to Treg cell antigen-specificity in functional assays. Here, we review the mechanisms controlling Foxp3 expression and the stability of the Treg cell lineage phenotype. Particular attention will be paid to the developmental and functional heterogeneity of human Treg cells, and how abrogating these mechanisms can lead to lineage instability and Treg cell dysfunction in human diseases like IPEX syndrome, type-1 diabetes, rheumatoid arthritis and cancer. This article is protected by copyright. All rights reserved.

KEYWORDS:

Regulatory T cells; antigen-specificity; cell therapy; human immunology; regulatory T cell dysfunction

PMID:
30864147
DOI:
10.1111/cei.13290

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