Human regulatory T cells in autoimmune diseases

Abstract

Human regulatory T cells (Tregs) play a critical role in preventing autoimmunity, and their failure contributes to autoimmune diseases. In recent years, our understanding of human Tregs has been greatly enhanced by improvements in the definition and isolation of pure human Tregs, as well as by the discovery of phenotypically and functionally distinct human Treg subsets. This progress has also yielded a better understanding of the mechanisms of human Treg suppression and the role of human Tregs in autoimmune diseases. An unexpected discovery is that human Tregs have considerable plasticity that allows them to produce the pro-inflammatory cytokine IL-17 under certain conditions. These recent advances highlight the importance of studying the roles of both mouse and human Tregs in autoimmunity.

Figure 1. Human Treg subsets and differentiation

The current understanding of human Treg subsets and differentiation is illustrated, with key phenotypic and functional features listed below each type of Treg. A) The human thymus produces naïve Tregs that travel to the periphery where they are activated by antigenic stimulation. Following activation, naïve Tregs proliferate and differentiate into HLA-DR⁻ effector Tregs, which have greater suppressive ability but are limited in proliferation ability and survival. Effector Tregs can further differentiate into HLA-DR⁺ terminal effector Tregs, which have the strongest, most rapid suppressive ability but also are highly apoptotic. B) In addition, human memory Tregs can be divided on the basis of ICOS expression into two subsets that differ in mechanism of suppression and signaling pathway involved in regulation of survival and proliferation. There does not appear to be any relationship between HLA-DR and ICOS expression in human Tregs. DC, dendritic cell; ICOS, inducible T cell co-stimulator; IL, interleukin; HLA-DR, human leukocyte antigen DR; TGF, transforming growth factor; CD, cluster of differentiation.

Figure 2. Human FoxP3+ HLA-DR⁻ Effector Tregs have the plasticity to produce the pro-inflammatory cytokine IL-17 in the presence of IL-1-beta and IL-6

FACS-sorted human HLA-DR⁻ effector Tregs (10⁴ cells/well) were stimulated in serum-free X-Vivo medium for five days with plate-bound CD3, soluble CD28, and IL-2 in the presence of exogenous IL-1-beta and IL-6. Supernatants and cells were harvested at 24-hour intervals and analyzed for IL-17 by ELISA (A) or mRNA expression of IL-17A (B) and RORC (C) by real-time polymerase chain reaction. Data are representative of two independent experiments. At the end of five days of culture, cells were pulsed for four hours with PMA/ionomycin and GolgiStop, and stained for intracellular IL-17 versus FoxP3 (D) or IFN-gamma (E). Data are representative of four independent experiments. These HLA-DR⁻ effector Tregs were also suppressive in a typical in vitro co-culture suppression assay (not shown). IL, interleukin; HLA-DR, human leukocyte antigen DR; CD, cluster of differentiation; FACS, fluorescence-activated cell sorting; ELISA, enzyme-linked immunosorbent assay; RORC, RAR-related orphan receptor C; PMA, phorbol myristate acetate; IFN, interferon. This research was originally published in Blood. Beriou G, Costantino CM, Ashley CW, Yang L, Kuchroo VK, Baecher-Allan C, Hafler DA: IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood 2009, 113:4240–4249. © the American Society of Hematology.