Mechanisms of human FoxP3⁺ T_reg cell development and function in health and disease

Regulatory T (T_reg ) cells represent an essential component of peripheral tolerance. Given their potently immunosuppressive functions that is orchestrated by the lineage-defining transcription factor forkhead box protein 3 (FoxP3), clinical modulation of these cells in autoimmunity and cancer is a promising therapeutic target. However, recent evidence in mice and humans indicates that T_reg cells represent a phenotypically and functionally heterogeneic population. Indeed, both suppressive and non-suppressive T_reg cells exist in human blood that are otherwise indistinguishable from one another using classical T_reg cell markers such as CD25 and FoxP3. Moreover, murine T_reg cells display a degree of plasticity through which they acquire the trafficking pathways needed to home to tissues containing target effector T (T_eff ) cells. However, this plasticity can also result in T_reg cell lineage instability and acquisition of proinflammatory T_eff cell functions. Consequently, these dysfunctional CD4⁺ FoxP3⁺ T cells in human and mouse may fail to maintain peripheral tolerance and instead support immunopathology. The mechanisms driving human T_reg cell dysfunction are largely undefined, and obscured by the scarcity of reliable immunophenotypical markers and the disregard paid to T_reg cell antigen-specificity in functional assays. Here, we review the mechanisms controlling the stability of the FoxP3⁺ T_reg cell lineage phenotype. Particular attention will be paid to the developmental and functional heterogeneity of human T_reg cells, and how abrogating these mechanisms can lead to lineage instability and T_reg cell dysfunction in diseases like immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, type 1 diabetes, rheumatoid arthritis and cancer.