Kidney transplantation (KT) is the best available treatment option for end-stage renal disease. However, the long-term success rate of KT is limited by acute or chronic allograft rejection due to progressive destruction caused by recognition of donor alloantigens by the recipient’s immune system [1]. Allograft rejection after KT is mediated mainly by helper T-cells. The Th1–Th2 balance is regarded as the major mechanism of rejection [2]. However, certain immunologic events occurring after KT cannot be explained solely by the Th1–Th2 balance. Therefore, the mechanism of rejection has been expanded to include T helper 17 (Th17) cells, which secrete the proinflammatory cytokine interleukin 17 (IL-17) [3].

Th17 cells were identified as a subset distinct from T helper type 1 and 2 cells in 2005 [3-5]. Th17 cells were first found to be clinically important in autoimmune disorders, and are now of interest in transplantation [6-8]. Indeed, Th17 cells and their associated cytokines play an important role in the development of acute and chronic allograft injury after organ transplantation [1,8-12]. For example, IL-17 messenger RNA (mRNA) and protein levels are elevated in animal models of acute rejection [13]. In KT, the IL-17 mRNA level is elevated in proximal tubular epithelial cells from allograft tissue with subclinical rejection [14]. Moreover, the IL‑17 protein level is elevated, and IL-17 mRNA is detectable, in kidney allografts with subclinical rejection [7]. Here, we review the findings on the role of Th17 cells in the development of acute or chronic rejection in KT, and discuss strategies to control the Th17 pathway.

Th17 cells secrete IL-17, which recruits monocytes and neutrophils and acts in synergy with other proinflammatory cytokines [3]. Transforming growth factor β, IL-6, and IL-1β mediate the induction of immature Th17 cells [15,16]. However, they have a different nuclear transcript factor profile compared to classical Th1 cells; i.e., RORγt (RAR-related orphan receptor γt) and signal transducer and activator of transcription 3 (STAT3) [3,17]. Finally, differentiation into effector Th17 cells is mediated by the IL-23–IL-23R interaction [18]. Mature Th17 cells produce IL-22, express C-C motif chemokine receptor (CCR)-6, -4, and -10, and do not produce IL-10 (Fig. 1) [19-21].

Acute allograft rejection is initiated by alloreactive T-cells primed in secondary lymphoid organs and recruited to the graft. The production of various proinflammatory cytokines by infiltrating cells is increased during acute kidney allograft rejection [22-24]. Therefore, diagnosis and staging of allograft rejection are based on the severity or pattern of immune cell infiltration and evidence of local immune system activation in allograft tissue [25-28]. Increased expression of IL-17 in local tissue is associated with allograft rejection in vivo [7,14,29]. Also, greater infiltration of Th17 cells compared to FOXP3+ (forkhead box P3+) regulatory T-cells (Tregs) is associated with both the severity of T-cell–mediated rejection (TCMR) and the subsequent clinical prognosis. A lower Treg/Th17 infiltration ratio is significantly associated with reduced allograft function and more severe interstitial and tubular injury [26]. Also, greater infiltration of Th17 cells is significantly associated with steroid-resistant rejection, incomplete recovery, recurrent TCMR, and a lower allograft survival rate after rejection. Several mechanisms have been suggested to underlie the above. First, renal epithelial cells exposed to IL-17 produce inflammatory mediators that stimulate early alloimmune responses [13]. Second, IL-17 induces neutrophil recruitment during severe rejection, as seen in biopsies [30]. Third, Th17 cells drive alloimmune responses by promoting lymphoid neogenesis [12]. Thus, Th17 cells induce stronger and more sustained alloimmune responses, which can result in severe injury to allograft tissue.

Th17 cells may be associated with severe allograft rejection. Therefore, we investigated whether Th17 cells are involved in chronic allograft dysfunction (CAD), which is the main cause of allograft failure. In human proximal renal tubular epithelial cells (HPRTEpiCs), IL-17 not only increases the production of markers of acute inflammation (IL-6 and IL-8) but also modulates the expression of profibrotic markers; e.g., CTGF (connective tissue growth factor) and ACTA-2 (α-actin 2) [31-33]. The proportion of peripheral blood Th17 cells from KT recipients with CAD was significantly increased in comparison to those of KT recipients with stable allograft function, irrespective of follow-up duration. Interestingly, the proportion of Th17 cells was higher in CAD patients than in transplant-naïve chronic kidney disease (CKD) patients, although renal function was lower in the CKD patients. This is important because uremia itself can increase the proportion of IL-17–producing effector T-cells [34]. Our results suggest that the immune response rather than renal dysfunction is responsible for the increased proportion of Th17 cells in patients with CAD (Fig. 2) [33].

The incidence of early allograft loss due to acute rejection can be significantly reduced by use of immune suppressants [35]. T-cells are suppressed by treatment with a combination of tacrolimus (Tac), mycophenolate mofetil, and steroid. In addition, induction therapy using basiliximab, an anti-CD25 monoclonal antibody, suppresses the proliferation of T-cells [1]. Although maintenance immune suppression can improve the allograft survival rate in the first year after KT, there has been little improvement in the long-term outcomes [36], suggesting that the currently used immune-suppressant regimen has limitations. Tac, the major immune-suppressant used in KT recipients, blocks Th1- and Th2-associated alloimmune responses [37-39]. In contrast, few animal studies have investigated the effect of calcineurin inhibitors (CNIs) on Th17 responses. In an animal model of heart transplantation, CNI did not suppress the Th17-associated response [40]. Both Th1 and Th2 cytokines are required to reduce the IL-17 level, while administration of an anti-Th1 or -Th2 cytokine antibody increases the IL-17 level [3]. Therefore, administration of Tac may actually enhance the Th17 response. Interestingly, the percentage of Th17 cells and production of IL‑17 by effector memory T-cells (TEM) are significantly (p < 0.05) increased at 3 months after KT compared to baseline, whereas the proportions of Th1/Th2 cells and TEM cells are decreased in the early post-transplantation period [41]. In addition, Tac suppresses Th1 and Th2 cells in a concentration-dependent manner, but even a high concentration has no effect on Th17 cells in vitro [41]. This suggests that Tac-based immunosuppression may be inadequate to suppress Th17 cells in KT recipients.

This review summarizes the role of Th17 cells in KT. The Th17 pathway plays an important role in various types of allograft injury. Tac-based immunosuppression has a limited impact on Th17-cell-induced allograft injury. Several recent studies, including ours, suggest that mTOR-targeted strategies could suppress the Th17 pathway, but the clinical relevance is unclear. Therefore, development of strategies targeting the Th17 pathway is required to improve allograft outcomes.