The role of retinoic acid‐related orphan receptor variant 2 and IL‐17 in the development and function of human CD4⁺ T cells

Abstract

Th17 cells are defined by their capacity to produce IL-17, and are important mediators of inflammation and autoimmunity. Human Th17 cells express high levels of the retinoic acid-related orphan receptor variant 2 (RORC2), but it is currently unclear whether expression of this transcription factor alone is sufficient to recapitulate all the known properties of Th17 cells. We used lentivirus-mediated transduction to investigate the role of RORC2 in defining aspects of the human Th17 cell lineage. Expression of RORC2 induced production of IL-17A, IL-22, IL-6 and TNF-a, a Th17-cell-associated chemokine receptor profile and upregulation of CD161. RORC2-transduced T cells were hypo-responsive to TCR-mediated stimulation, a property shared with ex vivo Th17 cells and overcome by addition of exogenous IL-2 or IL-15. Co-culture experiments revealed that RORC2-expressing cells were partially resistant to Treg cells since production of IL-17 and proliferation were not suppressed. Evidence that IL-17 stimulates CD41 T cells to produce IL-2 and proliferate suggested that the resistance of Th17 cells to Treg-mediated suppression may be partly attributed to IL-17 itself. These findings demonstrate that expression of RORC2 in T cells has functional consequences beyond altering cytokine production and provides insight into the factors regulating the development of human Th17 cells. 2]. More recently, a Th-cell lineage defined by its capacity to secrete IL-17 (Th17 cells) has been identified [3][4][5]. Mouse models have demonstrated that Th17 cells are critical for host defense against extracellular pathogens [6,7], whereas their aberrant expansion is linked to the pathogenesis of inflammatory autoimmune disorders [8]. Although Th17 cells produce several inflammatory cytokines, many of their effector functions are attributed to IL-17 production. IL-17 is known to recruit neutrophils and stimulate the production of pro-inflammatory cytokines, chemokines and antimicrobial peptides from a variety of immune and nonimmune cells [8][9][10][11]. Evidence from studies documenting increased levels of IL-17 in the peripheral blood and tissues of patients with rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease [12][13][14], and experimental models demonstrating a clear role for Th17 cells in the pathogenesis of these diseases, suggests that strategies to inhibit the 1480differentiation and/or function of Th17 cells in vivo may result in new therapies for inflammatory and autoimmune diseases.Most of the current knowledge regarding the phenotype and function of Th17 cells is based on studies carried out in mice. Mouse Th17 cells are defined by their capacity to produce IL-17 (IL-17A), IL-17F, TNF-a, IL-6 and IL-22, but not [15][16][17]. In vitro, TGF-b1 and IL-6 polarize naive mouse CD4 1 T cells into Th17 cells [18][19][20], whereas IL-23 is thought to be important for their expansion, survival, effector function and pathogenicity in vivo [20,21,22]. At the molecular level, at least five transcription factors are invol...

CD161 is a marker of all human IL‐17‐producing T‐cell subsets and is induced by RORC

“…Previous studies demonstrated that transduction of PB naïve T cells with RORC2 resulted in upregulation of CD161 and IL-17 [25]. UCB T lymphocytes.…”

Upstream Stimulating Factors Regulate the Expression of RORγT in Human Lymphocytes

“…To our knowledge, this represents the first report demonstrating the engagement of USFs in the regulation of RORgT expression. Expression of RORgT is a hallmark of Th17 development (8). Increased RORgT mRNA levels are associated with several human pathologies related to the presence of Th17-driven inflammatory processes (22,41).…”

“…Recently, the 7-oxygenated sterol was identified as an endogenous ligand modulating the function of this transcription factor (6). The expression of RORgT (also termed RORC2) has a very restricted pattern, and its product is predominantly found in immune organs, such as thymus, and in particular lineages of immune cells, such as immature doublepositive thymocytes and Th17 lymphocytes (2,7), where this transcription factor plays important functions in the maturation of a/b T cells and the differentiation of Th17 cells, respectively (2,8). Th17 cells are a subset of Th cells capable of expressing the proinflammatory cytokine IL-17 (9)(10)(11).…”

Human Th1 and Th17 Cells Exhibit Epigenetic Stability at Signature Cytokine and Transcription Factor Loci

“…For the time course of gene expression, cells were activated as described above but stimulated with anti-CD3/anti-CD28 beads (Invitrogen) to allow for quantitative RT-PCR analysis of gene expression at early time points. Finally, in some cases, ex vivo Th1 cells were transduced with control lentivirus (pCCL) or lentivirus-encoding RORC2 as previously described (30).…”

“…TBX21 (which encodes T-BET) is critical for Th1 differentiation (37,38), the RORC2 splice isoform of RORC is required for Th17 differentiation (30,(39)(40)(41), as is RORAd, which encodes RORad, and is reported to work in synergy with RORC2 to induce Th17 development (42). We examined three regions within transcription factor promoters (Supplemental Fig.…”