IL-23R and TCR signaling drives the generation of neonatal Vγ9Vδ2 T cells expressing high levels of cytotoxic mediators and producing IFN-γ and IL-17

Abstract

The immune system in early life is regarded as immature. However, the IL-12 family member IL-23 is highly produced upon TLR stimulation by neonatal DCs. Human adult Vγ9Vδ2 T cells can be stimulated specifically via their TCR by phosphoantigens (as the pathogen-derived HMB-PP) or agents and infections that lead to their endogenous accumulation (as the aminobisphosphonate zoledronate). As increasing evidence indicates that γδ T cells are especially important in early life, we investigated the effect of IL-23 on neonatal Vγ9Vδ2 T cells stimulated via their TCR. Zoledronate induced clear proliferation and IFN-γ production in neonatal Vγ9Vδ2 T cells. In contrast, HMB-PP did not elicit a distinct response unless at high concentrations. Addition of IL-23 to zoledronate enhanced the expression of IFN-γ and generated a distinct, IFN-γ-negative, neonatal Vγ9Vδ2 T cell population producing IL-17. Furthermore, IL-23 significantly enhanced the expression of a range of cytotoxic mediators (perforin, granzymes, granulysin). Although the costimulatory effect of IL-23 on IFN-γ and cytotoxic mediators was also observed within adult Vγ9Vδ2 T cells, the induction of an IL-17+IFN-γ- subset was unique to neonatal Vγ9Vδ2 T cells. In conclusion, neonatal DC-derived IL-23 combined with specific TCR signaling drives the generation of neonatal Vγ9Vδ2 T cells equipped with a range of cytotoxic mediators and distinct subpopulations producing IFN-γ and IL-17.

Interleukin 7 (IL-7) selectively promotes mouse and human IL-17–producing γδ cells

“…It is also striking that the major evocation of human IL-17-producing γδ cells is from CB. Interestingly, two studies using cytokines established to promote Th17 cells used CB to evoke small numbers of IL-17-producing γδ cells (46,47). γδ cells are functionally precocious relative to αβ T cells in mice and in humans, and one of their major biological contributions may be to protect neonates (29,48,49).…”

Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire

“…Indeed, one of the last cytokines to reach adult levels after birth is the Th1-promoting cytokine IL-12 (IL-12p70) (27). Originally proposed as a hypothesis by Adrian Hayday (1), there is increasing evidence, including our own results, that γδ T cells are important in early life (28)(29)(30)(31)(32)(33). Although in humans circulating T cells can be detected as early as 12.5 wk gestation, most information on T cells in early life, including γδ T cells, is derived from studies on cord blood at term delivery (>37 wk gestation) (34).…”

“…In addition, in comparison with Vγ9Vδ2 T cells in adults, Vγ9Vδ2 T cells in early life appear to have a higher threshold for activation by phosphoantigens such as HMB-PP and IPP, especially for the production of cytokines (this study and refs. 29,32,80).…”

Origins of γδ T Cell Effector Subsets: A Riddle Wrapped in an Enigma

“…Moreover, there are some suggestions that cytokines have different effects on the function of human gd T cells than they do on murine gd T cells. For example, stimulation of human adult Vg9Vd2 T cells with TCR agonists in the presence of IL-23 augments IFN-g production, not IL-17 production as it does in mouse (55). Accordingly, it will be critical to carefully determine whether the principles governing the acquisition of effector fate by gd T cells in model organisms also apply to human gd T cells.…”