Alternative titles; symbols
HGNC Approved Gene Symbol: RORC
SNOMEDCT: 1172892009;
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38): 1:151,806,071-151,831,802 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q21.3 | Immunodeficiency 42 | 616622 | Autosomal recessive | 3 |
The RORC gene is a member of the nuclear receptor gene superfamily, which encode transcriptional regulators that play critical roles during homeostasis and specific stages of development (summary by Hirose et al., 1994). Most nuclear receptors contain 5 major domains: an N-terminal A/B domain, a highly conserved DNA-binding (C) domain containing 2 zinc fingers, a hinge (D) region, a ligand-binding (E) domain, and an F domain at the C terminus (summary by Medvedev et al., 1997).
Using RT-PCR with degenerate primers based on the 2 most conserved regions of the C domain, Hirose et al. (1994) isolated a partial cDNA from human pancreas encoding a novel nuclear receptor. They then recovered skeletal muscle cDNAs containing the remainder of the coding region. By sequence analysis, Hirose et al. (1994) found that the predicted 560-amino acid protein, which they called ROR-gamma, belonged to the ROR/RZR nuclear receptor subfamily. ROR-gamma shares 50 to 51% sequence identity with RORA (600825) and RORB (601972). Northern blot analysis revealed that the 3.2-kb ROR-gamma transcript was expressed at the highest levels in skeletal muscle and at lower levels in various other tissues. Additional 5.2- and 7.2-kb transcripts were observed in thymus. Medvedev et al. (1997) stated that the amino acid sequences of mouse and human ROR-gamma are 88% identical.
Eberl and Littman (2004) showed that intestinal intraepithelial T lymphocytes (IELs) expressing the alpha-beta T-cell receptor (see 186880) are derived from precursors that express ROR-gamma-t, an orphan nuclear hormone receptor detected only in immature CD4(+)CD8(+) thymocytes, fetal lymphoid tissue-inducer (LTi) cells, and LTi-like cells in cryptopatches within the adult intestinal lamina propria. Using cell fate mapping, the authors found that all intestinal alpha-beta T cells are progeny of CD4(+)CD8(+) thymocytes, indicating that the adult intestine is not a significant site for alpha-beta T cell development. Eberl and Littman (2004) concluded that intestinal ROR-gamma-t(+) cells are local organizers of mucosal lymphoid tissue. Rocha (2005) commented on the paper by Eberl and Littman (2004), finding their experiments inconclusive and their interpretations inconsistent with previously published data. Eberl and Littman (2005) responded that while their findings did not exclude an extrathymic origin for some IELs, in particular, TCR-gamma-delta T cells, their contribution to the generation of the intestinal T cell pool is minimal in healthy mice.
Toward a system-level understanding of the transcriptional circuitry regulating circadian clocks, Ueda et al. (2005) identified clock-controlled elements on 16 clock and clock-controlled genes in a comprehensive surveillance of evolutionarily conserved cis elements and measurement of the transcriptional dynamics. Ueda et al. (2005) found that E boxes (CACGTG) and E-prime boxes (CACGTT) controlled the expression of Per1 (602260), Nr1d2 (602304), Per2 (603426), Nr1d1 (602408), Dbp (124097), Bhlhb2 (604256), and Bhlhb3 (606200) transcription following a repressor-precedes-activator pattern, resulting in delayed transcriptional activity. RevErbA/ROR-binding elements regulated the transcriptional activity of Arntl (602550), Npas2 (603347), Nfil3 (605327), Clock (601851), Cry1 (601933), and Rorc through a repressor-precedes-activator pattern as well. DBP/E4BP4-binding elements controlled the expression of Per1, Per2, Per3 (603427), Nr1d1, Nr1d2, Rora, and Rorb through a repressor-antiphasic-to-activator mechanism, which generates high-amplitude transcriptional activity. Ueda et al. (2005) suggested that regulation of E/E-prime boxes is a topologic vulnerability in mammalian circadian clocks, a concept that had been functionally verified using in vitro phenotype assay systems.
Silva-Santos et al. (2005) reported that double-positive T cells regulate the differentiation of early thymocyte progenitors and gamma-delta cells by a mechanism dependent on the transcription factor ROR-gamma-t and the lymphotoxin-beta receptor (LTBR; 600979). Silva-Santos et al. (2005) suggested the finding provokes a revised view of the thymus, in which lymphoid tissue induction-type processes coordinate the developmental and functional integration of the two T cell lineages.
Differentiation of both Th17 and T regulatory (Treg) cell types requires transforming growth factor-beta (TGFB; 190180), but depends on distinct transcription factors: ROR-gamma-t for Th17 cells and FOXP3 (300292) for Treg cells. Zhou et al. (2008) demonstrated that, together with proinflammatory cytokines, TGFB orchestrates Th17 cell differentiation in a concentration-dependent manner. At low concentrations, TGFB synergizes with IL6 (147620) and IL21 (605384) to promote IL23 receptor (IL23R; 607562) expression, favoring Th17 cell differentiation. High concentrations of TGFB repressed IL23R expression and favored FOXP3-positive Treg cells. ROR-gamma-t and Foxp3 are coexpressed in naive CD4+ T cells exposed to TGFB and in a subset of T cells in the small intestinal lamina propria of the mouse. In vitro, Tgfb-induced Foxp3 inhibited ROR-gamma-t function, at least in part through their interaction. Accordingly, lamina propria T cells that coexpressed both transcription factors produced less interleukin-17 (Il17a; 603149) than those that express ROR-gamma-t alone. Il6, Il21, and Il23 relieved Foxp3-mediated inhibition of ROR-gamma-t, thereby promoting Th17 cell differentiation. Therefore, Zhou et al. (2008) concluded that the decision of antigen-stimulated cells to differentiate into either Th17 or Treg cells depends on the cytokine-regulated balance of ROR-gamma-t and FOXP3.
To better understand the biology of lymph node formation and to identify human LTi cells, Cupedo et al. (2009) examined mesentery at 8 to 9 weeks of gestation, before circulation of CD3 (see 186740)-positive T cells begins at week 12. These mesenteric cells, as well as second-trimester lymph nodes, contained CD127 (IL7R; 146661)-positive cells that did not express other lineage markers, including CD19 (107265) for B cells, CD3 for T cells, CD56 (NCAM1; 116930) and CD16 (FCGR3A; 146740) for NK cells, and CD14 (158120) for monocytes. Quantitative PCR and RT-PCR analysis indicated that the CD127-positive/lineage-negative cells also expressed high levels of RORC, as well as LTA (153440), RANKL (602642), and RANK (603499). Human CD127-positive/RORC-positive LTi cells produced IL17 (IL17A; 603149) and IL22 (605330), but not IFNG (147570), in vitro and in postnatal tonsil cells, and they differentiated into NK cells, but not other lymphoid lineages. Cupedo et al. (2009) concluded that human LTi cells are committed immature NK-cell precursors that interact with LTBR and TNFR (191190) on mesenchymal stem cells in early lymph node anlagen and induce lymph node organogenesis.
Ghoreschi et al. (2010) showed that Th17 differentiation can occur in the absence of TGF-beta (190180) signaling. Neither IL6 nor IL23 (see 605580) alone efficiently generated Th17 cells; however, these cytokines in combination with IL1-beta (147720) effectively induced IL17 production in naive precursors, independently of TGF-beta. Epigenetic modification of the IL17A, IL17F (606496), and RORC promoters proceeded without TGF-beta-1, allowing the generation of cells that coexpressed ROR-gamma-t and Tbet (TBX21; 604895). Tbet+ROR-gamma-t+Th17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred Th17 cells generated with IL23 without TGF-beta-1 were pathogenic in this disease model. Ghoreschi et al. (2010) concluded that their data indicated an alternative mode for Th17 differentiation, and that, consistent with genetic data linking IL23R with autoimmunity, their findings reemphasized the importance of IL23 and therefore may have therapeutic implications.
LTi cells initiate the development of lymphoid tissues through the activation of local stromal cells in a process similar to inflammation. LTi cells express the nuclear hormone receptor ROR-gamma-t, which also directs the expression of the proinflammatory cytokine interleukin-17 in T cells. Sawa et al. (2010) demonstrated that LTi cells are part of a larger family of proinflammatory ROR-gamma-t-positive innate lymphoid cells (ILCs) that differentiate from distinct fetal liver ROR-gamma-t-positive precursors. The fate of ROR-gamma-t-positive ILCs is determined by mouse age, and after birth favors the generation of cells involved in intestinal homeostasis and defense. Contrary to ROR-gamma-t-positive T cells, however, ROR-gamma-t-positive ILCs develop in the absence of microbiota. Sawa et al. (2010) concluded that ROR-gamma-t-positive ILCs evolve to preempt intestinal colonization by microbial symbionts.
By performing a chemical screen with an insect cell-based reporter system, Huh et al. (2011) identified the cardiac glycoside digoxin as a specific inhibitor of ROR-gamma-t transcriptional activity. Digoxin inhibited murine Th17 cell differentiation without affecting differentiation of other T cell lineages and was effective in delaying the onset and reducing the severity of autoimmune disease in mice. At high concentrations, digoxin is toxic for human cells, but nontoxic synthetic derivatives 20,22-dihydrodigoxin-21,23-diol and digoxin-21-salicylidene specifically inhibited induction of IL17 in human CD4+ T cells. Using these small-molecule compounds, Huh et al. (2011) demonstrated that ROR-gamma-t is important for the maintenance of IL17 expression in mouse and human effector T cells, and suggested that derivatives of digoxin can be used as chemical templates for the development of ROR-gamma-t-targeted therapeutic agents that attenuate inflammatory lymphocyte function and autoimmune disease.
Solt et al. (2011) presented SR1001, a high-affinity synthetic ligand--the first in a new class of compound--that is specific to both ROR-alpha (600825) and ROR-gamma-t and which inhibits Th17 cell differentiation and function. SR1001 binds specifically to the ligand-binding domains of ROR-alpha and ROR-gamma-t, inducing a conformational change within the ligand-binding domain that encompasses the repositioning of helix-12 and leads to diminished affinity for coactivators and increased affinity for corepressors, resulting in suppression of the receptors' transcriptional activity. SR1001 inhibited the development of murine Th17 cells, as demonstrated by inhibition of interleukin-17A gene expression and protein production. Furthermore, SR1001 inhibited the expression of cytokines when added to differentiated murine or human Th17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Solt et al. (2011) concluded that their data demonstrated the feasibility of targeting the orphan receptors ROR-alpha and ROR-gamma-t to inhibit specifically Th17 cell differentiation and function, and indicated that this novel class of compound has potential utility in the treatment of autoimmune diseases.
ILCs expressing the transcription factor ROR-gamma-t induce the postnatal formation of intestinal lymphoid follicles and regulate intestinal homeostasis. ROR-gamma-t-positive ILC express the aryl hydrocarbon receptor (AHR; 600253), a highly conserved, ligand-inducible transcription factor believed to control adaptation of multicellular organisms to environmental challenges. In mice, Kiss et al. (2011) showed that Ahr is required for the postnatal expansion of intestinal ROR-gamma-t-positive ILC and the formation of intestinal lymphoid follicles. Ahr activity within ROR-gamma-t-positive ILC could be induced by dietary ligands such as those contained in vegetables of the family Brassicaceae. Ahr-deficient mice were highly susceptible to infection with Citrobacter rodentium, a mouse model for attaching and effacing infections. Kiss et al. (2011) concluded that their results established a molecular link between nutrients and the formation of immune system components required to maintain intestinal homeostasis and resistance to infections.
Using predominantly wildtype and Hif1a (603348)-/- mouse T cells, Dang et al. (2011) showed that Hif1a was specifically required for differentiation of naive T cells into Th17 cells. Hif1a interacted directly with Ror-gamma-t and acetyltransferase p300 (EP300; 602700) at the Il17 promoter, and all 3 factors were required for optimum Il17 expression. Simultaneously, Hif1a downregulated differentiation of naive T cells into Treg cells by directing proteasomal degradation of the Treg-dependent transcription factor Foxp3 by a mechanism that was independent of Hif1a transcriptional activity. Differentiation of Th17 cells and loss of Treg cells was enhanced in cultures subjected to hypoxic conditions. Knockout of Hif1a in mouse T cells rendered mice highly resistant to Mog (159465)-induced experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis (see 126200). Dang et al. (2011) concluded that HIF1A has a role in immune responses by controlling the balance between Th17 and Treg cells.
Santarlasci et al. (2012) noted that Th17 cells have a critical pathogenic role in chronic inflammatory disorders, but they are rarely found in inflammatory sites. Santarlasci et al. (2012) found that, unlike Th1 cells, human CD161 (KLRB1; 602890)-positive Th17 precursor cells did not proliferate and produce IL2 (147680) in response to anti-CD3 (see CD3E; 186830)/anti-CD28 (186760) stimulation. Th17 cells also proliferated poorly in response to IL2, in part due to lower expression of the transcription factors JUN (165160), FOS (164810), and NFATC1 (600489) and reduced surface expression of CD3E and CD3Z (CD247; 186780). Microarray and small interfering RNA analyses revealed high expression of IL4I1 (609742) in Th17 precursor cells and showed that IL4I1 upregulation was strictly dependent on RORC, the Th17 master regulatory gene. Flow cytometric analysis revealed that Th17 cells also exhibited high CD28 expression that was RORC dependent, and stimulation of CD28 alone induced IL17 production and IL4I1 mRNA upregulation. Th17 cells from synovial fluid of patients with juvenile idiopathic arthritis (see 604302) also expressed higher levels of IL4I1 and CD28 than did Th1 cells. Santarlasci et al. (2012) concluded that the rarity of human Th17 cells in inflamed tissues results from RORC-dependent mechanisms that limit their expansion and, therefore, reduce their potential to cause damage.
Klose et al. (2013) provided evidence that the transcription factor Tbet (604895) determines the fate of a distinct lineage of CCR6 (601835)-negative ROR-gamma-t-positive ILCs. Postnatally emerging CCR6-ROR-gamma-t+ ILCs upregulated Tbet, and this was controlled by cues from the commensal microbiota and IL23 (605580). In contrast, CCR6+ROR-gamma-t+ ILCs, which arise earlier during ontogeny, did not express Tbet. Tbet instructed the expression of Tbet target genes such as interferon-gamma and of the natural cytotoxicity receptor NKp46 (604530). Mice genetically lacking Tbet showed normal development of CCR6-ROR-gamma-t innate lymphoid cells, but these cells could not differentiate into NKp46-expressing ROR-gamma-t+ ILCs (i.e., IL22-producing natural killer cells) and failed to produce interferon-gamma. The production of interferon-gamma by Tbet-expressing CCR6-ROR-gamma-t+ ILCs was essential for the release of mucus-forming glycoproteins required to protect the epithelial barrier against Salmonella enterica infection. Klose et al. (2013) concluded that coexpression of Tbet and ROR-gamma-t, which is also found in subsets of IL17-producing T-helper cells, may be an evolutionarily conserved transcriptional program that originally developed as part of the innate defense against infections but that also confers an increased risk of immune-mediated pathology.
Yu et al. (2013) showed that the transcription factor NFIL3 (605327) suppresses Th17 cell development by directly binding and repressing the ROR-gamma-t promoter. NFIL3 links Th17 cell development to the circadian clock network through the transcription factor REV-ERB-alpha (NR1D1; 602408). Accordingly, Th17 lineage specification varies diurnally and is altered in Rev-erb-alpha-null mice. Light-cycle disruption elevated intestinal Th17 cell frequencies and increased susceptibility to inflammatory disease. Yu et al. (2013) concluded that lineage specification of this key immune cell is under direct circadian control.
Using flow cytometric analysis of tonsil- or lamina propria-derived CD127-positive/RORC-positive innate lymphoid cells (ILCs, or LTi cells), Glatzer et al. (2013) determined that IL22 was produced only by the NKp44 (NCR2; 604531)-positive subset. Anti-NKp44-mediated triggering of NKp44, but not other receptors on ILCs, elicited TNF (191160) and IL2, but not IL22 or GMCSF (CSF2; 138960) production. Stimulation of ILCs with cytokines resulted in production of IL22, but only low TNF. Engagement of both NKp44, through antibody or influenza virus, and cytokine receptors synergistically led to ILC activation and enhanced IL22 production. Glatzer et al. (2013) concluded that NKp44-positive/RORC-positive/CD127-positive ILCs can be activated without cytokines and can switch between IL22 and TNF production, depending on the triggering stimulus.
Van de Pavert et al. (2014) showed that mouse fetal type 3 innate lymphoid (ILC3) cells are controlled by cell-autonomous retinoic acid (RA) signaling in utero, which presets the immune fitness in adulthood. The authors found that embryonic lymphoid organs contain ILC progenitors that differentiate locally into mature LTi cells. Local LTi cell differentiation was controlled by maternal retinoid intake and fetal RA signaling acting in a hematopoietic cell-autonomous manner. RA controlled LTi cell maturation upstream of the transcription factor ROR-gamma-t. Accordingly, enforced expression of Rorgt restored maturation of LTi cells with impaired RA signaling, whereas RA receptors directly regulated the Rorgt locus. Finally, van de Pavert et al. (2014) established that maternal levels of dietary retinoids control the size of secondary lymphoid organs and the efficiency of immune responses in the adult offspring. Van de Pavert et al. (2014) concluded that their results revealed a molecular link between maternal nutrients and the formation of immune structures required for resistance to infection in the offspring.
Ohnmacht et al. (2015) reported that microbiota-induced regulatory T cells express the nuclear hormone receptor ROR-gamma-t and differentiate along a pathway that also leads to Th17 cells. In the absence of ROR-gamma-t+ regulatory T cells (Tregs), Th2-driven defense against helminths is more efficient, whereas Th2-associated pathology is exacerbated. Thus, Ohnmacht et al. (2015) concluded that the microbiota regulates type 2 responses through the induction of type 3 ROR-gamma-t+ Tregs and Th17 cells and acts as a key factor in balancing immune responses at mucosal surfaces.
Sefik et al. (2015) found that symbiotic members of the human gut microbiota induce a distinct Treg population in the mouse colon, which constrains immunoinflammatory responses. This induction requires the transcription factor Ror-gamma, paradoxically, in that Ror-gamma is thought to antagonize FoxP3 (300292) and to promote Th17 cell differentiation. Ror-gamma's transcriptional footprint differs in colonic Tregs and Th17 cells and controls important effector molecules. Ror-gamma, and the Tregs that express it, contribute substantially to regulating colonic Th1/Th17 inflammation. Sefik et al. (2015) concluded that marked context-specificity of Ror-gamma results in very different outcomes even in closely related cell types.
Zhang et al. (2017) demonstrated that TGF-beta (190180) enables Th17 cell differentiation by reversing SKI (164780)-SMAD4 (600993)-mediated suppression of the expression of ROR-gamma-t. Zhang et al. (2017) found that, unlike wildtype T cells, SMAD4-deficient T cells differentiate into Th17 cells in the absence of TGF-beta signaling in a RORC-dependent manner. Ectopic SMAD4 expression suppresses RORC expression and Th17 cell differentiation of SMAD4-deficient T cells. However, TGF-beta neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the RORC locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGF-beta stimulation. SKI controls histone acetylation and deacetylation of the RORC locus and Th17 cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the RORC locus, RORC expression, and Th17 cell differentiation in a SMAD4-dependent manner. Therefore, Zhang et al. (2017) concluded that TGF-beta-induced disruption of SKI reverses SKI-SMAD4-mediated suppression of ROR-gamma-t to enable Th17 cell differentiation.
Hang et al. (2019) screened a library of bile acid metabolites and identified 2 distinct derivatives of lithocholic acid (LCA), 3-oxoLCA and isoalloLCA, as T cell regulators in mice. 3-OxoLCA inhibited the differentiation of Th17 cells by directly binding to the key transcription factor ROR-gamma-t and isoalloLCA increased the differentiation of Treg cells through the production of mitochondrial reactive oxygen species (mitoROS), which led to increased expression of FOXP3. The isoalloLCA-mediated enhancement of Treg cell differentiation required an intronic Foxp3 enhancer, the conserved noncoding sequence (CNS)3; this represented a mode of action distinct from that of previously identified metabolites that increase Treg cell differentiation, which require CNS1. The administration of 3-oxoLCA and isoalloLCA to mice reduced Th17 cell differentiation and increased Treg cell differentiation, respectively, in the intestinal lamina propria. Hang et al. (2019) concluded that their data suggested mechanisms through which bile acid metabolites control host immune responses, by directly modulating the balance of Th17 and Treg cells.
Medvedev et al. (1997) found that the mouse Rorc gene contains 11 exons and spans more than 21 kb.
By analysis of somatic cell hybrids, Hirose et al. (1994) mapped the ROR-gamma gene to human chromosome 1. Using fluorescence in situ hybridization, Medvedev et al. (1997) refined the map position to 1q21. They mapped the ROR-gamma gene in mouse to band 3F2.1-2.2.
In affected members of 3 unrelated consanguineous families with immunodeficiency-42 (IMD42; 616622), Okada et al. (2015) identified 3 different homozygous mutations in the RORC gene (602943.0001-602943.0003). The mutations, which were found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the families. All 3 mutations, including 2 nonsense mutations and 1 missense mutation, resulted in a complete loss of function of both the ROR-gamma and ROR-gamma-t isoforms, as demonstrated by in vitro functional expression studies. Patient lymphocytes showed impaired production of IL17A (603149), IL17F (606496), and IL22 (605330) at both the mRNA and protein levels, which likely contributed to chronic candidal infections. Although patient cells did not show impaired production of IFN-gamma (IFNG; 147570) in response to polyclonal stimulation, there was a selective defect in IFNG production by certain T-cell populations specifically in response to treatment with BCG plus IL12 (see 161560), which may have accounted for the mycobacterial disease in these patients.
Most developing thymocytes undergo apoptosis because they do not interact productively with major histocompatibility complex (MHC) molecules. A thymus-specific isoform of RORC, termed ROR-gamma-t (RORGT), inhibits the expression of Fas ligand (TNFSF6; 134638) and IL2 (147680). Sun et al. (2000) generated Rorc-deficient mice and found that although they were fertile and phenotypically normal, they had reduced overall as well as double-positive (DP) CD4 (186940)-positive/CD8 (see 186910)-positive and single-positive CD4-positive thymic cell numbers and did not express Bclxl (see BCL2L1; 600039). The DP cells underwent spontaneous apoptosis at a more rapid rate than those in wildtype mice. The Rorc-null mice had reduced amounts of CDKN1B (600778) and correspondingly greater CDK2 (116953) activity. Expression of Bclxl restored most aspects of thymocyte development and increased survival. Although Rorc-deficient mice had normal export of T lymphocytes to the periphery and normal splenic architecture, they completely lacked lymph nodes and Peyer patches, possibly due to the absence of Rorc-expressing CD4-positive/CD45 (151460)-positive progenitor cells.
To identify the physiologic functions of the retinoid-related orphan receptor gamma, Kurebayashi et al. (2000) generated mice deficient in ROR-gamma function by targeted disruption. Homozygous-null mice lacked peripheral and mesenteric lymph nodes and Peyer patches, indicating that RORC gene expression is indispensable for lymph node organogenesis. Although the spleen was enlarged, its architecture was normal. The thymus of Rorc -/- mice contained 74.4% fewer thymocytes than that of wildtype mice. Rorc -/- thymocytes placed in culture exhibited dramatic increase in the rate of 'spontaneous' apoptosis. The observations indicated that ROR-gamma is essential for lymphoid organogenesis and plays an important regulatory role in thymopoiesis.
Using FACS analysis, Zhang et al. (2003) showed that splenomegaly in Rorg -/- mice was due to increased numbers of resting B lymphocytes, with only marginal increases in T cells and macrophages. In contrast, peripheral blood lymphocyte levels were comparable to those in wildtype mice. B-lymphocyte development was normal in both bone marrow and spleens of Rorg -/- mice. Experiments with bone marrow chimeras using Rorg -/- or Rag2 (179616) -/- mice as recipients and wildtype or Rorg -/- mice as donors, respectively, showed that there was no defect in lymphocyte homeostasis in Rorg -/- mice, but they appeared to have a defect in the exit of lymphocytes from the spleen.
Eberl et al. (2004) generated mice expressing green fluorescent protein in exon 1 of the gene encoding Rorgt. During fetal life, Rorgt was expressed exclusively in CD4-positive and CD4-negative lymphoid tissue inducer (LTi) cells, which are associated with the development of lymph nodes and Peyer patches. LTi cells provide essential factors, including lymphotoxin alpha-1 (153440)/beta-2 (600978), for activation of the mesenchyma in the lymph node and Peyer patch anlagen. Rorgt-deficient mice lacked all lymph nodes and Peyer patches, as well as LTi cells, a phenotype similar to that observed in Id2 (600386) -/- mice. However, unlike Id2 -/- mice, Rorgt -/- mice retained CD45-positive cells, CD11b (120980)-positive cells, and MHC class II-positive cells.
RORG, which is broadly expressed, and RORGT, which is expressed exclusively in immune system cells, are both encoded by the RORC gene through the use of different promoters and differ only in their N termini. Ivanov et al. (2006) found that a subset of mouse lamina propria T cells expressed Rorgt and, using mice lacking Rorgt, they showed that Rorgt was required for expression of Il17. Mice lacking Rorgt had 10-fold fewer Il17-positive cells in intestinal lamina propria compared with wildtype mice. Forced expression of Rorgt in naive T cells induced expression of Il17 and Il17f (606496). FACS and RT-PCR analyses of mice lacking Il6 (147620), which have normal T-cell numbers, defective induction of autoimmunity, and increased susceptibility to a variety of pathogens, showed that Il6 was required for expression of both Rorgt and Il17. Rorc -/- mice were less susceptible to experimental allergic encephalomyelitis, as were Rag2-deficient mice that received adoptively transferred cells from Rorc -/- mice. Ivanov et al. (2006) concluded that RORGT is the transcription factor that directs differentiation of inflammatory Th17 cells.
The article by Huang et al. (2015) identifying Ddx5 (180630) as an Ror-gamma-t-interacting protein in mouse Th17 cells and concluding that gly270 in the long noncoding RNA Rmrp (157660) was critical for Ddx5-Ror-gamma-t complex assembly and for recruitment of Rmrp to Ror-gamma-t loci to coordinate the Th17 effector program was retracted because key aspects of the original results could not be replicated.
In 3 sibs, born of consanguineous Israeli Palestinian parents, with immunodeficiency-42 (IMD42; 616622), Okada et al. (2015) identified a homozygous C-to-T transition in the RORC gene, resulting in a ser38-to-leu (S38L) substitution at a highly conserved residue in the DNA-binding domain of the ROR-gamma isoform (the mutation corresponds to S17L in the ROR-gamma-t isoform). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family and was found only once in the ExAC database. In vitro functional expression studies in HEK293T cells showed that the mutation abolished DNA binding of the RORC isoforms to binding sites in the promoter of the IL17A gene (603149), consistent with a complete loss of function.
In a girl, born of consanguineous Chilean parents, with immunodeficiency-42 (IMD42; 616622), Okada et al. (2015) identified a homozygous C-to-T transition in the RORC gene, resulting in a gln329-to-ter (Q329X) substitution predicted to result in a truncated protein lacking part of the ligand-binding domain in the ROR-gamma isoform (the mutation corresponds to Q308X in the ROR-gamma-t isoform). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family, and was not found in the ExAC or dbSNP databases, in an in-house database of more than 3,000 exomes, or in 1,052 CEPH controls. In vitro functional expression studies in HEK293T cells showed that the mutation abolished DNA binding of the RORC isoforms to binding sites in the promoter of the IL17A gene (603149), consistent with a complete loss of function.
In 3 sibs, born of consanguineous parents from Saudi Arabia, with immunodeficiency-42 (IMD42; 616622), Okada et al. (2015) identified a homozygous C-to-T transition in the RORC gene, resulting in a gln441-to-ter (Q441X) substitution, predicted to result in a truncated protein lacking part of the ligand-binding domain in the ROR-gamma isoform (the mutation corresponds to Q420X in the ROR-gamma-t isoform). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. It was not found in the ExAC or dbSNP databases, in an in-house database of more than 3,000 exomes, or in 1,052 CEPH controls. In vitro functional expression studies in HEK293T cells showed that the mutation abolished DNA binding of the RORC isoforms to binding sites in the promoter of the IL17A gene (603149), consistent with a complete loss of function.
Cupedo, T., Crellin, N. K., Papazian, N., Rombouts, E. J., Weijer, K., Grogan, J. L., Fibbe, W. E., Cornelissen, J. J., Spits, H. Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells. Nature Immun. 10: 66-74, 2009. [PubMed: 19029905] [Full Text: https://doi.org/10.1038/ni.1668]
Dang, E. V., Barbi, J., Yang, H.-Y., Jinasena, D., Yu, H., Zheng, Y., Bordman, Z., Fu, J., Kim, Y., Yen, H.-R., Luo, W., Zeller, K., Shimoda, L., Topalian, S. L., Semenza, G. L., Dang, C. V., Pardoll, D. M., Pan, F. Control of Th17/T-reg balance by hypoxia-inducible factor 1. Cell 146: 772-784, 2011. [PubMed: 21871655] [Full Text: https://doi.org/10.1016/j.cell.2011.07.033]
Eberl, G., Littman, D. R. Thymic origin of intestinal alpha-beta T cells revealed by fate mapping of ROR-gamma-t(+) cells. Science 305: 248-251, 2004. [PubMed: 15247480] [Full Text: https://doi.org/10.1126/science.1096472]
Eberl, G., Littman, D. R. Response to comment on 'Thymic Origin of Intestinal alpha-beta T Cells Revealed by Fate Mapping of ROR-gamma-delta+ Cells.' (Commentary) Science 308: 1553 only, 2005. [PubMed: 15947157] [Full Text: https://doi.org/10.1126/science.1107558]
Eberl, G., Marmon, S., Sunshine, M.-J., Rennert, P. D., Choi, Y., Littman, D. R. An essential function for the nuclear receptor ROR-gamma-t in the generation of fetal lymphoid tissue inducer cells. Nature Immun. 5: 64-73, 2004. [PubMed: 14691482] [Full Text: https://doi.org/10.1038/ni1022]
Ghoreschi, K., Laurence, A., Yang, X.-P., Tato, C. M., McGeachy, M. J., Konkel, J. E., Ramos, H. L., Wei, L., Davidson, T. S., Bouladoux, N., Grainger, J. R., Chen, Q., and 9 others. Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467: 967-971, 2010. [PubMed: 20962846] [Full Text: https://doi.org/10.1038/nature09447]
Glatzer, T., Killig, M., Meisig, J., Ommert, I., Luetke-Eversloh, M., Babic, M., Paclik, D., Bluthgen, N., Seidl, R., Seifarth, C., Grone, J., Lenarz, M., Stolzel, K., Fugmann, D., Porgador, A., Hauser, A., Karlas, A., Romagnani, C. ROR-gamma-t+ innate lymphoid cells acquire a proinflammatory program upon engagement of the activating receptor NKp44. Immunity 38: 1223-1235, 2013. [PubMed: 23791642] [Full Text: https://doi.org/10.1016/j.immuni.2013.05.013]
Hang, S., Paik, D., Yao, L., Kim, E., Trinath, J., Lu, J., Ha, S., Nelson, B. N., Kelly, S. P., Wu, L., Zheng, Y., Longman, R. S., Rastinejad, F., Devlin, A. S., Krout, M. R., Fischbach, M. A., Littman, D. R., Huh, J. R. Bile acid metabolites control TH17 and Treg cell differentiation. Nature 576: 143-148, 2019. Note: Erratum: Nature 579: E7, 2020. Electronic Article. [PubMed: 31776512] [Full Text: https://doi.org/10.1038/s41586-019-1785-z]
Hirose, T., Smith, R. J., Jetten, A. M. ROR-gamma: the third member of ROR/RZR orphan receptor subfamily that is highly expressed in skeletal muscle. Biochem. Biophys. Res. Commun. 205: 1976-1983, 1994. [PubMed: 7811290] [Full Text: https://doi.org/10.1006/bbrc.1994.2902]
Huang, W., Thomas, B., Flynn, R. A., Gavzy, S. J., Wu, L., Kim, S. V., Hall, J. A., Miraldi, E. R., Ng, C. P., Rigo, F., Meadows, S., Montoya, N. R., and 9 others. DDX5 and its associated lncRNA Rmrp modulate T(H)17 cell effector functions. Nature 528: 517-522, 2015. Note: Erratum: Nature 533: 130 only, 2016. Retraction: Nature 562: 150 only, 2018. [PubMed: 26675721] [Full Text: https://doi.org/10.1038/nature16193]
Huh, J. R., Leung, M. W. L., Huang, P., Ryan, D. A., Krout, M. R., Malapaka, R. R. V., Chow, J., Manel, N., Ciofani, M., Kim, S. V., Cuesta, A., Santori, F. R., Lafaille, J. J., Xu, H. E., Gin, D. Y., Rastinejad, F., Littman, D. R. Digoxin and its derivatives suppress Th17 cell differentiation by antagonizing ROR-gamma-t activity. Nature 472: 486-490, 2011. [PubMed: 21441909] [Full Text: https://doi.org/10.1038/nature09978]
Ivanov, I. I., McKenzie, B. S., Zhou, L., Tadokoro, C. E., Lepelley, A., Lafaille, J. J., Cua, D. J., Littman, D. R. The orphan nuclear receptor ROR-gamma-t directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126: 1121-1133, 2006. [PubMed: 16990136] [Full Text: https://doi.org/10.1016/j.cell.2006.07.035]
Kiss, E. A., Vonarbourg, C., Kopfmann, S., Hobeika, E., Finke, D., Esser, C., Diefenbach, A. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 334: 1561-1565, 2011. [PubMed: 22033518] [Full Text: https://doi.org/10.1126/science.1214914]
Klose, C. S. N., Kiss, E. A., Schwierzeck, V., Ebert, K., Hoyler, T., d'Hargues, Y., Goppert, N., Croxford, A. L., Waisman, A., Tanriver, Y., Diefenbach, A. A T-bet gradient controls the fate and function of CCR6(-)ROR-gamma-t(+) innate lymphoid cells. Nature 494: 261-265, 2013. [PubMed: 23334414] [Full Text: https://doi.org/10.1038/nature11813]
Kurebayashi, S., Ueda, E., Sakaue, M., Patel, D. D., Medvedev, A., Zhang, F., Jetten, A. M. Retinoid-related orphan receptor gamma (ROR-gamma) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc. Nat. Acad. Sci. 97: 10132-10137, 2000. [PubMed: 10963675] [Full Text: https://doi.org/10.1073/pnas.97.18.10132]
Medvedev, A., Chistokhina, A., Hirose, T., Jetten, A. M. Genomic structure and chromosomal mapping of the nuclear orphan receptor ROR-gamma (RORC) gene. Genomics 46: 93-102, 1997. [PubMed: 9403063] [Full Text: https://doi.org/10.1006/geno.1997.4980]
Ohnmacht, C., Park, J.-H., Cording, S., Wing, J. B., Atarashi, K., Obata, Y., Gaboriau-Routhiau, V., Marques, R., Dulauroy, S., Fedoseeva, M., Busslinger, M., Cerf-Bensussan, N., Boneca, I. G., Voehringer, D., Hase, K., Honda, K., Sakaguchi, S., Eberl, G. The microbiota regulates type 2 immunity through ROR-gamma-t+ T cells. Science 349: 989-993, 2015. [PubMed: 26160380] [Full Text: https://doi.org/10.1126/science.aac4263]
Okada, S., Markle, J. G., Deenick, E. K., Mele, F., Averbuch, D., Lagos, M., Alzahrani, M., Al-Muhsen, S., Halwani, R., Ma, C. S., Wong, N., Soudais, C., and 39 others. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. Science 349: 606-613, 2015. [PubMed: 26160376] [Full Text: https://doi.org/10.1126/science.aaa4282]
Rocha, B. Comment on 'Thymic Origin of Intestinal alpha-beta T Cells Revealed by Fate Mapping of ROR-gamma-delta+ Cells.' (Commentary) Science 308: 1553 only, 2005. [PubMed: 15947157] [Full Text: https://doi.org/10.1126/science.1107558]
Santarlasci, V., Maggi, L., Capone, M., Querci, V., Beltrame, L., Cavalieri, D., D'Aiuto, E., Cimaz, R., Nebbioso, A., Liotta, F., De Palma, R., Maggi, E., Cosmi, L., Romagnani, S., Annunziato, F. Rarity of human T helper 17 cells is due to retinoic acid orphan receptor-dependent mechanisms that limit their expression. Immunity 36: 201-214, 2012. [PubMed: 22326581] [Full Text: https://doi.org/10.1016/j.immuni.2011.12.013]
Sawa, S., Cherrier, M., Lochner, M., Satoh-Takayama, N., Fehling, H. J., Langa, F., Di Santo, J. P., Eberl, G. Lineage relationship analysis of ROR-gamma-t+ innate lymphoid cells. Science 330: 665-669, 2010. [PubMed: 20929731] [Full Text: https://doi.org/10.1126/science.1194597]
Sefik, E., Geva-Zatorsky, N., Oh, S., Konnikova, L., Zemmour, D., McGuire, A. M., Burzyn, D., Ortiz-Lopez, A., Lobera, M., Yang, J., Ghosh, S., Earl, A., Snapper, S. B., Jupp, R., Kasper, D., Mathis, D., Benoist, C. Individual intestinal symbionts induce a distinct population of ROR-gamma+ regulatory T cells. Science 349: 993-997, 2015. [PubMed: 26272906] [Full Text: https://doi.org/10.1126/science.aaa9420]
Silva-Santos, B., Pennington, D. J., Hayday, A. C. Lymphotoxin-mediated regulation of gamma-delta cell differentiation by alpha-beta T cell progenitors. Science 307: 925-928, 2005. [PubMed: 15591166] [Full Text: https://doi.org/10.1126/science.1103978]
Solt, L. A., Kumar, N., Nuhant, P., Wang, Y., Lauer, J. L., Liu, J., Istrate, M. A., Kamenecka, T. M., Roush, W. R., Vidovic, D., Schurer, S. C., Xu, J., Wagoner, G., Drew, P. D., Griffin, P. R., Burris, T. P. Suppression of Th17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 472: 491-494, 2011. [PubMed: 21499262] [Full Text: https://doi.org/10.1038/nature10075]
Sun, Z., Unutmaz, D., Zou, Y.-R., Sunshine, M. J., Pierani, A., Brenner-Morton, S., Mebius, R. E., Littman, D. R. Requirement for ROR-gamma in thymocyte survival and lymphoid organ development. Science 288: 2369-2373, 2000. [PubMed: 10875923] [Full Text: https://doi.org/10.1126/science.288.5475.2369]
Ueda, H. R., Hayashi, S., Chen, W., Sano, M., Machida, M., Shigeyoshi, Y., Iino, M., Hashimoto, S. System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nature Genet. 37: 187-192, 2005. [PubMed: 15665827] [Full Text: https://doi.org/10.1038/ng1504]
van de Pavert, S. A., Ferreira, M., Domingues, R. G., Ribeiro, H., Molenaar, R., Moreira-Santos, L., Almeida, F. F., Ibiza, S., Barbosa, I., Goverse, G., Labao-Almeida, C., Godinho-Silva, C., and 13 others. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature 508: 123-127, 2014. [PubMed: 24670648] [Full Text: https://doi.org/10.1038/nature13158]
Yu, X., Rollins, D., Ruhn, K. A., Stubblefield, J. J., Green, C. B., Kashiwada, M., Rothman, P. B., Takahashi, J. S., Hooper, L. V. Th17 cell differentiation is regulated by the circadian clock. Science 342: 727-730, 2013. [PubMed: 24202171] [Full Text: https://doi.org/10.1126/science.1243884]
Zhang, N., Guo, J., He, Y.-W. Lymphocyte accumulation in the spleen of retinoic acid receptor-related orphan receptor gamma-deficient mice. J. Immun. 171: 1667-1675, 2003. [PubMed: 12902464] [Full Text: https://doi.org/10.4049/jimmunol.171.4.1667]
Zhang, S., Takaku, M., Zou, L., Gu, A., Chou, W., Zhang, G., Wu, B., Kong, Q., Thomas, S. Y., Serody, J. S., Chen, X., Xu, X., Wade, P. A., Cook, D. N., Ting, J. P. Y., Wan, Y. Y. Reversing SKI-SMAD4-mediated suppression is essential for T(H)17 cell differentiation. Nature 551: 105-109, 2017. [PubMed: 29072299] [Full Text: https://doi.org/10.1038/nature24283]
Zhou, L., Lopes, J. E., Chong, M. M. W., Ivanov, I. I., Min, R., Victora, G. D., Shen, Y., Du, J., Rubtsov, Y. P., Rudensky, A. Y., Ziegler, S. F., Littman, D. R. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing ROR-gamma-t function. Nature 453: 236-240, 2008. [PubMed: 18368049] [Full Text: https://doi.org/10.1038/nature06878]