Human CD25highFoxp3pos regulatory T cells differentiate into IL-17–producing cells

Abstract

The effector T-cell lineage shows great plasticity. Th17 cells are acknowledged to be instrumental in the response against microbial infection, but are also associated with autoimmune inflammatory processes. Here, we report that human regulatory T cells ( IntroductionIn mice, IL-17A (IL-17)-producing T cells have been established as an important T-helper (Th) effector lineage, clearly distinct from the Th1 or Th2 lineage. 1,2 Infectious disease mouse models indicate that IL-17-producing cells (Th17) mediate protection against extracellular pathogens. 3-5 However, on the downside, Th17 cells also appear to be the driving force in the pathogenesis of several autoimmune diseases. 2,6 Furthermore, mouse studies showed that differentiation of Th17 cells from naive CD4 T cells requires the concomitant activity of IL-6 and transforming growth factor-␤ (TGF␤). [7][8][9] The key transcription factor driving Th17 cell differentiation is the orphan nuclear receptor ROR␥t, which is needed for constitutive expression of In in vivo studies in mice, IL-17-and ROR␥t-expressing cells were shown to be present in the lung and digestive mucosal compartments, 11 and especially throughout the intestinal lamina propria. 10 In humans, IL-17 is associated with many inflammatory disorders such as rheumatoid arthritis, asthma, multiple sclerosis, lupus, Crohn disease, and allograft rejection. 3,[12][13][14][15] Recently, human ROR␥t-positive IL-17-producing T cells were identified under physiologic conditions in peripheral blood and tonsils, [15][16][17] being contained within the CCR6 ϩ (CCR4 ϩ )CD4 ϩ memory T-cell population. 15,16 Most recent data show that human Th17 differentiation, distinct from mouse Th17 development, is under control of IL-1␤, 19 In mice, the development of Th17 cells was described to be linked to that of regulatory T cells (Tregs) in a reciprocal fashion, whereby under the influence of TGF␤, IL-6 levels determine the outcome. 8,9 In vitro, activated Tregs promoted Th17 cell differentiation from CD4 T cells, 9,20 likely through their production of TGF␤.In addition, in vivo the transfer of Treg enhanced IL-17 production in a mouse model of systemic autoimmune disease. 21 Next, to this reciprocal relationship, it was recently demonstrated that IL-17-producing cells directly develop from mouse Tregs. 20 This is a remarkable finding, because Tregs are typically associated with T-cell tolerance and immune homeostasis. 22 Different Treg subsets have been described, and even within the naturally occurring CD4 pos CD25 high Foxp3 pos population heterogeneity is evident. This heterogeneity reflects differences in differentiation or developmental stage, trafficking properties, and suppressor capacity. [23][24][25] Although the lineage differentiation of helper T cells is very well accepted, that of Tregs is only scarcely recognized. In humans, naive and memory-like CD4 pos CD25 pos Foxp3 pos Treg have been defined in peripheral blood, discriminated by the expression of CD45 isoforms CD45RA and CD45RO. [25][26][27][28] Al...

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

“…150). Paradoxically, pan-inhibition of HDAC activity prevents loss of FOXP3 expression and IL-17 induction by human T Reg cells cultured with T H 17 cell-inducing cytokines 17 .…”

“…In the metastable state, individual human or mouse T cells, assessed directly ex vivo, can co-express many polarizing transcription factors, cytokines and chemokine receptors [13][14][15] . Reprogramming between distinct CD4 + T cell subsets can be observed in human and mouse T cells under certain conditions in vitro [16][17][18][19] or in mice in vivo on transferring highly purified popu lations of cells [20][21][22][23][24][25] . By using lineage-tracing systems in mice, in which cells are engineered to express Cre recombinase under the control of transcriptional elements that regulate key polarization factors (such as cytokines or transcription factors) and a fluorescent protein reporter of Cre activity, endogenously polarized CD4 + T cells from many subsets have been found to change phenotype during their lifespan [26][27][28][29] .…”

“…In addition, the pleiotropic cytokine IL-27 can induce IL-10 expression by various inflammatory subsets to promote regulatory functions, as well as induce the generation of type 1 regulatory T (T R 1) cells de novo [42][43][44] . Conversely, the treatment of tT Reg cells from mice or humans with the T H 17 cellinducing cytokines IL-6, IL-1β and IL-23 (especially in combination) can destabilize FOXP3 expression and induce IL-17 production in vitro 17,18 , and STAT3 (which is activated in response to these cytokines) is required for reprogramming 45 . Expression of IFNγ and T-bet in FOXP3 + T Reg cells in response to IL-12 has been widely observed in mice and humans 14,[46][47][48] , and this may help T Reg cells to control T H 1 cell-based immunopathology 49 .…”

The role of all-trans retinoic acid in the biology of Foxp3+ regulatory T cells

“…The key reason is that inflammatory cytokines, such as IL-6, TNF-a and IL-1, may decrease Foxp3 expression and subsequently reduce the functional activity of nTreg cells. 22,23,[32][33][34][35][36] THE STABILITY OF TREG CELL SUBSETS Recent studies demonstrated that nTreg cells from both mouse and human are instable and dysfunctional under inflammatory conditions. 7,32,34,35,37,38 These cells not only lose their suppressive ability after encountering inflammatory environments, but they can convert into pathogenic cells that may actually accelerate the inflammatory process.…”

CD200-CD200R signaling suppresses anti-tumor responses independently of CD200 expression on the tumor

“…Tolerance to exogenous antigens can be conferred by transfer of Treg cells from tolerized animals into naive recipients (Unger et al, 2003b). However, in inflammatory conditions Treg cells can change their phenotype and start to produce interleukin (IL)-17, mimicking Th17 cells (Koenen et al, 2008;Zhou et al, 2008;Baban et al, 2009;Chung et al, 2009;Murphy and Stockinger, 2010). Th17 cells specifically express the transcription factor RORg and are mostly known for their instrumental role in the development of autoimmune diseases (Fouser et al, 2008).…”