Separating the wheat from the chaff: Making sense of Treg heterogeneity for better adoptive cellular therapy

Regulatory T (Treg) cells are essential for immunological tolerance and can be used to suppress unwanted or excessive immune responses through adoptive cellular therapy. It is increasingly clear that many subsets of Treg cells exist, which have different functions and reside in different locations. Treg cell therapies may benefit from tailoring the selected subset to the tissue that must be protected as well as to characteristics of the immune response that must be suppressed, but little attention is given to this topic in current therapies. Here, we will discuss how three major axes of heterogeneity can be discerned among the Treg cell population, which determine function and lineage fidelity. A first axis relates to the developmental route, as Treg cells can be generated from immature T cells in the thymus or from already mature Tconv cells in the immunological periphery. Heterogeneity furthermore stems from activation history (naïve or effector) and location (lymphoid or peripheral tissues). Each of these axes bestows specific properties on Treg cells, which are further refined by additional processes leading to yet further variation. A critical aspect impacting on Treg cell heterogeneity is TCR specificity, which determines when and where Treg cells are generated as well as where they exhibit their effector functions. We will discuss the implications of this heterogeneity and the role of the TCR for the design of next generation adoptive cellular therapy with Treg cells.