The natural and the inducible: interleukin (IL)-17-producing γδ T cells

Abstract

γδ T cells are the major initial interleukin (IL)-17 producers in acute infections. Recent studies have indicated that some γδ T cells have IL-17-producing capabilities without explicit induction of an immune response. They are preferentially localized in barrier tissues and are likely to originate from fetal γδ thymocytes. In addition, γδ T cells present in the secondary lymphoid organs will mature and differentiate to produce IL-17 after antigen encounter in an immune response. Based on these studies, we propose that there are two different sets of IL-17-producing γδ T cells (Tγδ17) referred to as the 'natural' and the 'inducible' Tγδ17 cells. This review focuses on recent publications leading to the delineation of these two types of cells and their implied roles in host immune defense.

Figure 1

Model for development of natural Tγδ17 (nTγδ17) cells according to Haas et al. [REF]. Commitment and differentiation of nTγδ17 cells is restricted to the fetal thymus. It requires the absence of specific TCR ligation and depends on signaling via lymphotoxin-β-receptor (LTβR), Transforming growth factor-beta (TGF-β), B lymphoid kinase (Blk), and the Notch-Hes1 pathway. nTγδ17 cells exit the thymus as CCR6⁺CD27⁻CD44^hiIL-23R⁺ effector cells and persist as a self-renewing pool in peripheral tissues. There, specific TCR triggering and/or IL-23 and IL-1 induce IL-17 production of nTγδ17 cells.

Figure 2

Model for induction of Tγδ17 (iTγδ17) cells according to Zeng et al. [REF]. Specific microbial antigen such as phycoerythrin (PE) can activate uncommitted naive CD62L^hiCD44^lo γδ T cells in secondary lymphoid tissues via their TCR. This TCR-ligation stimulates their rapid acquisition of effector phenotype and effector functions including IL-17 production, without extensive clonal expansion. Concurrently induced responsiveness to IL-23 and IL-1 further perpetuates pro-inflammatory IL-17 production by iTγδ17 cells.