Plasticity Of Th17 Cells Research Articles

Human tumor‐infiltrating Th17 cells have the capacity to differentiate into IFN‐γ+ and FOXP3+ T cells with potent suppressive function

Accumulating evidence suggests that Th17 cells and Tregs may exhibit development plasticity and that CD4(+) Tregs can differentiate into IL-17-producing T cells; however, whether Th17 cells can reciprocally convert into Tregs has not been described. In this study, we generated Th17 clones from tumor-infiltrating T lymphocytes (TILs). We showed that Th17 clones generated from TILs can differentiate into IFN-γ-producing and FOXP3(+) cells after in vitro stimulation with OKT3 and allogeneic peripheral blood mononuclear cells. We further demonstrated that T-cell receptor (TCR) engagement was responsible for this conversion, and that this differentiation was due to the epigenetic modification and reprogramming of gene expression profiles, including lineage-specific transcriptional factor and cytokine genes. In addition to expressing IFN-γ and FOXP3, we showed that these differentiated Th17 clones mediated potent suppressive function after repetitive stimulation with OKT3, suggesting that these Th17 clones had differentiated into functional Tregs. We further demonstrated that the Th17-derived Tregs, unlike naturally occurring CD4(+) CD25(+) Tregs, did not reconvert back into Th17 cells even under Th17-biasing cytokine conditions. These results provide the critical evidence that human tumor-infiltrating Th17 cells can differentiate into Tregs and indicate a substantial developmental plasticity of Th17 cells.

Plasticity of Th17 cells and therapeutic conundrum

CD4+ T cells are highly heterogeneous with respect to their phenotype, secretion of effector molecules, transcription factors and functions. In the periphery, CD4+ T cells can be polarized into distinct subsets under the influence of antigen presenting cells and cytokine milieu. Recently, Th17 cells that express lineage-specific transcription factor RORC (ROR?t in mice) and produce cytokines IL-17A and IL-17F were identified as distinct lineage of CD4+ T cells [1]. Th17 cells are important to clear extracellular bacteria and fungi. However, when tolerance mechanisms breach, these Th17 cells can also mediate inflammation and can play critical role in the pathogenesis of several autoimmune diseases. In fact, a large number of autoimmune and inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, asthma, lupus, psoriasis and others are characterized by an aberrant activation of Th17 cells and hyper-expression of Th17 inflammatory mediators such as IL-17, IL-21, IL-22, CCL20 and GM-CSF [2,3]. Therefore, Th17 cells are one of the potential targets to treat these diseases.

Genetic controls of Th17 cell differentiation and plasticity

CD4+ T lymphocytes play a major role in regulation of adaptive immunity. Upon activation, naïve T cells differentiate into different functional subsets. In addition to the classical Th1 and Th2 cells, several novel effector T cell subsets have been recently identified, including Th17 cells. There has been rapid progress in characterizing the development and function of Th17 cells. Here I summarize and discuss on the genetic controls of their differentiation and emerging evidence on their plasticity. This information may benefit understanding and treating immune diseases.

Are Th17 Cells an Appropriate New Target in the Treatment of Rheumatoid Arthritis?

Th17 cells play crucial roles not only in host defense but also in many human autoimmune diseases and corresponding animal models. Although many of the fundamental principles regarding Th17 biology have been rapidly elucidated in mice, there remain numerous controversies regarding the differentiation, plasticity, and pathogenicity of human Th17 cells. In this review, we consider these open questions in comparison to what has already been clarified in mice, and discuss the potential impact of discoveries related to the Th17 pathway on the development of new therapeutic strategies in Th17 driven autoimmune diseases, specifically rheumatoid arthritis.

The transient nature of the Th17 phenotype

CD4(+) Th lymphocytes represent a heterogeneous population of cells that play an essential role in adaptive immunity. In addition to type 1 (Th1) and type 2 (Th2) cells, a third subset of CD4(+) Th effector cells has recently been discovered, named type 17 (Th17) because of its unique ability to produce interleukin (IL)-17. Initial studies in mice suggested that Th17 cells are the pathogenic cells in autoimmune disorders, whereas Th1 cells are protective. Studies in humans have demonstrated the plasticity of Th17 cells and their ability to convert to Th1 cells. This Th17 to Th1 cell plasticity has also been confirmed in mice and, furthermore, it was found that Th17 cells appear to be pathogenic only when they shift to Th1 cells. A study in this issue of the European Journal of Immunology uses an IL-17 fate mapping mouse strain, which permits the identification of the cells that have been IL-17 producers, to provide definitive evidence that Th17 cells, either generated in vitro or in vivo, represent a transient phenotype that tend to convert into IFN-γ-producing cells. Our Commentary discusses this interesting point in light of previous data suggesting the same concept.

Do studies in humans better depict Th17 cells?

AbstractCD4+ T helper (Th) lymphocytes represent a heterogeneous population of cells. In addition to type 1 (Th1) and type 2 (Th2) cells, another subset of CD4+ effector Th cells has been discovered and named as Th17, because of its unique ability to produce interleukin (IL)–17. Studies in mice initially suggested that Th17 cells are the pathogenic cells in autoimmune disorders, whereas Th1 cells may behave rather as protective. Subsequent studies in humans demonstrated the plasticity of Th17 cells and their possibility to shift to Th1. The plasticity of Th17 to Th1 cells has recently been confirmed in mice, where it was found that Th17 cells seem to be pathogenic only when they shift to Th1 cells. Studies in humans also showed that Th17 cells are different than in mice because all of them express CD161 and exclusively originate from CD161+ precursors present in umbilical cord blood and newborn thymus. While murine Th17 cells develop in response to IL-6, IL-1, and transforming growth factor (TGF)–β, human Th17 cells originate from these CD161+ precursors in response to IL-1β and IL-23, the need for TGF-β being controversial. Thus, we believe that studies in humans have better depicted human Th17 cells than studies in mice.

Cutting Edge: In Vitro Generated Th17 Cells Maintain Their Cytokine Expression Program in Normal but Not Lymphopenic Hosts

Upon activation, naive CD4(+) T cells differentiate into effector Th cell subsets. The stability and plasticity of effector Th cells have not been well understood. In this study we used an IL-17F-red fluorescent protein reporter mouse to analyze the plasticity of Th17 cells in vitro and in vivo. We found that in vitro generated Th17 cells poorly maintained their differentiation program in vitro and could be reprogrammed into other T cell lineages. Moreover, upon transfer into lymphopenic hosts, Th17 cells rapidly lost their IL-17 expression and were converted into Th1 cells independently of IL-7 signaling. However, Th17 cells maintained their phenotypes well in normal animals, even in the absence of Ag and inflammation. These results, although suggesting the plasticity of Th17 cells, also indicate active maintenance of their program in vivo.