RORγt plays an essential role in establishing and maintaining adaptive immune responses by enabling the formation of secondary and tertiary lymphoid organs and by regulating thymic T cell development and TH17 cell differentiation. The requirement of RORγt for the development of several innate lymphoid cells underscores its importance in innate immunity as well. Moreover, a strong association with autoimmunity makes RORγt an important drug target.
Introduction of RORγt
RORγt, an immune cell-specific isoform of ROR, has attracted much attention as the key transcription factor of TH17 cells, mediating the expression of the pro-inflammatory cytokines IL17A and IL-17F in both mouse and human. The various roles of RORγt in immune homeostasis and immunopathology have been the subject of several excellent reviews. RORγt, by its nature as a ligand-dependent transcription factor, has become a prime target for pharmacological intervention to repress the function of TH17 cells and their downstream cytokines.
RORγt and γδ17 T Cells
Although RORγt is necessary for the differentiation of TH17 cells, it is not essential for the development of γδ17 progenitors in the fetal thymus. However, consistent with its ability to bind to and transactivate the Il17 promoter, RORγt is important for optimal IL-17 production. Interestingly, despite being developed, RORγt deficient γδ T-cells cannot persist in the periphery, suggesting a potentially critical role for RORγt in the homeostasis of adult γδ17 T-cells. This could be either cell-extrinsic or cell-intrinsic. RORγt is necessary for the development of all secondary lymphoid tissues. Thus, upon export in the periphery, γδ17 T-cells may not have the appropriate microenvironment to sustain homeostasis (cell-extrinsic). In the cell-intrinsic scenario, RORγt may be important for the survival of γδ17 cells by regulating the levels of the anti-apoptotic protein Bcl-xL. Recent data have demonstrated that via its interaction with LxxLL containing nuclear co-factors RORγt can function as a transcriptional repressor and suppress the expression of BTLA. Therefore, an alternative cell-intrinsic hypothesis is that loss of RORγt results in aberrant expression of BTLA and perhaps other co-inhibitory receptors (such as LAG-3; Bekiaris/Ware, unpublished observations) leading to sustained inhibition of homeostatic expansion.
Fig.1 BTLA and RORγt mediated control of γδ17 T-cells. (Bekiaris, 2014)
RORγt and IL-17 Production from Activated γδ T Cells
The transcription factors RORγt and signal transducer and activator of transcription 3 (STAT3) are associated with IL-17 production from both αβ T cells and activated γδ T cells. Interestingly, there appears to be a higher constitutive expression of RORγt in γδ T cells as compared with other T cells. Furthermore, RORγt-deficient mice have a defect in IL-17 production. However, it should be noted that RORγt expression is not confined to IL-17-producing cells, indicating that this is not the only transcriptional factor involved in IL-17 production. In contrast, the PU.1 transcription factor has been shown to negatively regulate proliferation and IL-17 production by γδ T cells. γδ T cells are capable of IL-17 production before exiting the thymus. It also has been reported that thymic γδ T cells that are antigen-naive or bind antigen with low affinity, produce IL-17, while antigen-experienced γδ T cells that bind antigen with high affinity produce IFN-γ. This observation was confirmed and extended by a recent study showing that Skint-1, a molecule expressed by thymic and epidermal epithelial cells, activates Egr3 which, in turn, promotes differentiation of IFN-γ-secreting γδ T cells and suppresses the development of RORγt+ IL-17-secreting γδ T cells.
Fig.2 Innate IL-17 production by γδ T cells. (Sutton, 2012)
In the past research, enormous progress has been made in studying RORγt functions in immune responses, innate immunity, and the potential as a drug target. Still lagging behind but rapidly evolving is the understanding of the functions of RORγt expressed from γδ T cells nowadays. Future research will allow scientists to further deepen our understanding of RORγt biology and to fully realize the potential of RORγt in the clinic.
- Bekiaris, V.; et al. Mixing signals: Molecular turn ons and turn offs for innate γδ T-cells. Front Immunol. 2014, 5: 654.
- Sutton, C. E.; et al. Il-17-producing γδ T cells and innate lymphoid cells. Eur J Immunol. 2012, 42(9): 2221-31.