The importance of regulatory T-cell heterogeneity in maintaining self-tolerance

Abstract

CD4(+) Forkhead box protein 3 (Foxp3)(+) regulatory T cells (Tregs) are the major cell type that mediates dominant tolerance in the periphery. Over the past decade, extensive study of Tregs has revealed that these cells express substantial heterogeneity to maintain tolerance and regulate immune responses. Tregs possess heterogeneity with respect to their origin and processes for development, functional activity, migratory pattern, and activation status. Some of the same environmental cues and molecular pathways utilized to generate specialized T-effector cells are also integrated by Tregs to colocalize and fine-tune suppressive mechanisms to optimally regulate and restrain distinctive self and antigen-specific T-cell responses. Here, we review our current understanding and significance of Treg heterogeneity in maintaining peripheral immune tolerance. We also highlight recent work from our laboratory that has studied the extent phenotypically distinct Treg subsets are related to each other and expand in an ordered fashion to give rise to highly activated short-lived Klrg1(+) suppressor cells to optimize immune regulation and maintain homeostasis of the Treg compartment.

Keywords: Klrg1; Tregs; effector; memory; subsets; tolerance.

Fig. 1

Model of activation and development of Klrg1⁺ Tregs.

Fig. 2. Inter-relationship between Treg subsets

Adult TCRα^−/− mice were adoptively transferred with a mixture (1:10) of RFP⁺ Tregs from purified subsets (Fr1-3, Klrg1⁻) and Treg-depleted conventional CD4⁺ T cells. The persistence and phenotype of the donor cells were assessed 3-4 weeks post-transfer. (A) Expansion of the donor T-conventional and Treg cells where the total numbers of injected (input) and recovered (output) cells from the spleen were enumerated. (B) Spleen and MLN were examined for donor Tregs as a fraction of the total CD4⁺ T-cell compartment. (C) The phenotype of donor Tregs from recipients that received the indicated fractions of Klrg1-depleted Fr1, Fr2, or Fr3 RFP⁺ donor Treg cells. Shown at the top is the expression of CD62L and CD69 and at the bottom is the expression of Klrg1 by donor Tregs.