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.