RORγt

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 T_H17 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 T_H17 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 T_H17 cells and their downstream cytokines.

RORγt and γδ¹⁷ T Cells

Although RORγt is necessary for the differentiation of T_H17 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RORγt results in aberrant expression of BTLA and perhaps other co-inhibitory receptors (such as LAG-3; Bekiaris/Ware, unpublished observations) leading to sustained inhibition of homeostatic expansion.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.

References

1. Bekiaris, V.; et al. Mixing signals: Molecular turn ons and turn offs for innate γδ T-cells. Front Immunol. 2014, 5: 654.
2. Sutton, C. E.; et al. Il-17-producing γδ T cells and innate lymphoid cells. Eur J Immunol. 2012, 42(9): 2221-31.