The Jekyll and Hyde story of IL17-Producing γδT Cells

Abstract

In comparison to conventional αβT cells, γδT cells are considered as specialized T cells based on their contributions in regulating immune response. γδT cells sense early environmental signals and initiate local immune-surveillance. The development of functional subtypes of γδT cells takes place in the thymus but they also exhibit plasticity in response to the activating signals and cytokines encountered in the extrathymic region. Thymic development of Tγδ1 requires strong TCR, CD27, and Skint-1 signals. However, differentiation of IL17-producing γδT cells (Tγδ17) is independent of Skint-1 or CD27 but requires notch signaling along with IL6 and TGFβ cytokines in the presence of weak TCR signal. In response to cytokines like IL23, IL6, and IL1β, Tγδ17 outshine Th17 cells for early activation and IL17 secretion. Despite expressing similar repertoire of lineage transcriptional factors, cytokines, and chemokine receptors, Tγδ17 cells differ from Th17 in spatial and temporal fashion. There are compelling reasons to consider significant role of Tγδ17 cells in regulating inflammation and thereby disease outcome. Tγδ17 cells regulate mobilization of innate immune cells and induce keratinocytes to secrete anti-microbial peptides thus exhibiting protective functions in anti-microbial immunity. In contrast, dysregulated Tγδ17 cells inhibit Treg cells, exacerbate autoimmunity, and are also known to support carcinogenesis by enhancing angiogenesis. The mechanism associated with this dual behavior of Tγδ17 is not clear. To exploit, Tγδ17 cells for beneficial use requires comprehensive analysis of their biology. Here, we summarize the current understanding on the characteristics, development, and functions of Tγδ17 cells in various pathological scenarios.

Keywords: IL17; Tγδ17; cancer; infection; inflammation; γδT cell.

Figure 1

Overview of Tγδ17 cells development. The figure illustrates the differentiation of Tγδ17 cells from T cell progenitors in the murine thymus (A–C) and from naïve γδT cells in periphery in human (D). Progenitor T cells differentiate through double negative stage 1 (DN1) to DN stage 4 (A). The decision of αβ or γδ TCR expression takes place at early T cells precursor (from DN2 or DN3 stage) as showed by dashed line. The thymocytes expressing αβ TCR develop into double-positive thymocytes, which support differentiation of functional subtypes of γδT cells called as transconditioning. DP thymocytes secrete LTβL, which support differentiation of Tγδ17. The DP αβ thymocytes then exit the thymus as mature single positive T cells (either CD4⁺ or CD8⁺ T cells) (A). The functional programing of γδT cells is determined by TCR signal and/or other related signals. TCR signal, interaction with Skint-1 from epithelial cells, downregulation of SOX13, and signaling through CD27/CD70 divert γδ thymocytes toward IFNγ-producing phenotype (Tγδ1), which migrate to periphery (B). Conversely, signaling through Notch receptor maintain Sox13 levels with increase in Hes1 and RORγt expression induce γδ thymocytes to produce IL17. Progression of γδ thymocytes to Tγδ17 cells is independent of signaling through Skint-1 and/or CD27 but require inputs from IL6 and TGFβ. The natural Tγδ17 cells developed in thymus migrate to tissue or periphery (C). In human, naïve γδT cells, which exit thymus, can also differentiate into Tγδ17 cells in presence of TCR signal and cytokines such as IL6, IL1β, IL23, and TGFβ (D).

Figure 2

Functions of Tγδ17 cells in pathological conditions. (A) Tγδ17 cells promote infiltration of neutrophils and monocytes/macrophages to the site of inflammation through chemokines. (B) IL17 secreted by Tγδ17 cells induces keratinocytes to produce anti-microbial peptides such as β defensins and protect host in infections. (C) Dysregulated Tγδ17 cells in autoimmune diseases inhibit Treg expansion and its ability to suppress autoreactive cell, thereby exacerbating the disease. (D) The inflammatory condition in arthritis is worsened by IL17, which foster osteoclast formation through induction of RANKL. Tγδ17 cells are involved in bone resorption and enhance joint inflammation. (E) Human Tγδ17 cells support MDSC migration, survival, and promote their suppressive functions through IL17, GMCSF, and IL8. MDSCs also form feedback loop and promote Tγδ17 differentiation through IL23 and IL1β. (F) Tγδ17 cells secrete IL17 and induce tumorigenesis by their proangiogenic activity. (G) Murine Tγδ17 cells recruit small peritoneal macrophages to the tumor bed, which induce angiogenesis.