Absence of donor Th17 leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease

Abstract

Th17 is a newly identified T-cell lineage IntroductionAcute graft-versus-host disease (GVHD), the leading cause of morbidity and mortality of allogeneic hematopoietic cell transplantation (HCT), is a complex process involving dysregulation of inflammatory cytokine cascades and distorted donor cellular response against host alloantigens. 1 Activation of alloreactive donor T cells is initiated by host antigen-presenting cells (APCs), especially dendritic cells (DCs). [2][3][4][5] Much effort has been devoted to understand how the polarization of donor T cells to the Th1 or Th2 phenotype contributes to acute GVHD. In some experimental models, it has been shown that Th1 cells augment and Th2 cells ameliorate acute GVHD. 1,[6][7][8] However, it was also reported that the absence of Th1 cytokine interferon (IFN)-␥ augments acute GVHD, but loss of the Th2 cytokine interleukin (IL)-4 reduces acute GVHD. 9,10 Furthermore, donor T cells deficient in either Th1 or Th2 differentiation were shown to be able to mediate acute GVHD. 11 Therefore, the role of donor T-cell subsets in GVHD pathogenesis is still controversial. It is likely that T-cell subsets other than Th1 or Th2 play a role in mediating acute GVHD.Th17 is a newly identified T-cell lineage that secretes the proinflammatory cytokine IL-17. 12 Naive CD4 ϩ T cells differentiate into Th17 cells in the presence of IL-6 and transforming growth factor (TGF)-␤. [13][14][15] Th17 cells express IL-23 receptor, and IL-23, an IL-12 family member, is critical for their survival and proliferation. [16][17][18] Orphan nuclear receptor ROR␥t is the key transcription factor that orchestrates differentiation of the Th17 lineage. 19 Interestingly, it has been shown that naive CD8 ϩ T cells can also differentiate into IL-17-producing T cells in the same culture condition as CD4 ϩ T cells. 20 One of the important functions of IL-17 is to coordinate local tissue inflammation through the up-regulation of proinflammatory cytokines and chemokines. 21 Thus, IL-17 has been implicated in a critical role in the host defense against a series of extracellular pathogens, such as Klebsiella pneumoniae and Candida albicans. 22,23 However, uncontrolled Th17 cells have been reported to be involved in autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and experimental autoimmune encephalomyelitis (EAE). [24][25][26][27] In contrast, IL-17 has also been shown to have some regulatory effect in mediating tissue inflammation. It was reported that IL-17 inhibited CD4 ϩ T-cell activation, 28 suppressed the tissue expression of chemokines (eg, CCL5 and CCL27), 29,30 and down-regulated VCAM-1 expression on epithelial cells. 31 Moreover, neutralization of IL-17 was reported to aggravate dextran sulfate sodium-induced colitis in mice, 32 and absence of IL-17 augmented allergic asthma. 33 The role of Th17 cells in GVHD pathogenesis is still unknown. In the current study, we demonstrated that IL-17 Ϫ/Ϫ donor T cells showed an augmented Th1 differentiation and IFN-␥ production and induc...

Differential Regulation of Chemokines by IL-17 in Colonic Epithelial Cells

“…Second, IL-17 produced by Th17 cells as they accumulate at the site of inflammation may negatively regulate the recruitment of Th1 cells. Consistent with the notion of a feedback loop in which IL-23 and IL-17 negatively regulate the IL-12/IFN-␥ network, the administration of an anti-IL-17 mAb worsens the course of dextran sodium sulfate-induced colitis, the elimination of IL-23 worsens the development of T cell-mediated trinitrobenzene sulfonic acid-induced colitis, and donor Th17 cells negatively regulate Th1 differentiation and ameliorate acute graftvs-host disease (51)(52)(53). Similarly, in a mouse model of allergic asthma, IL-17 functions as a negative regulator by repressing expression of the eosinophil chemokine CCL11 (eotaxin) and the Th2 chemokine CCL17 (thymus-and activation-regulated chemokine or TARC) (27).…”

A single nucleotide polymorphism of IL-17 gene in the recipient is associated with acute GVHD after HLA-matched unrelated BMT

“…Several mouse model experiments have revealed that transfer of IL-17-producing cells induced acute GVHD, [33][34][35] whereas in contrast there is a report 31 showing that donor IL-17-producing cells ameliorated acute GVHD. Host DCs are critical in the initiation of acute GVHD, [52][53][54] leading to a hypothesis that IL-17-producing cells could modify the function of host DCs through unknown mechanisms.…”

“…[21][22][23][24][25][26][27][28][29] Moreover, several reports have so far shown that Th17 cells and IL-17 has a significant impact on the development of acute GVHD in mouse models. [30][31][32][33][34][35] Recent reports have shown association of SNPs in the IL-17 gene with autoimmune diseases such as rheumatoid arthritis and ulcerative colitis. [36][37][38][39] The promoter SNP of the IL-17 gene, rs2275913 (G197A), was found to be associated with the susceptibility of rheumatoid arthritis in the Norwegian population 38 as well as that of ulcerative colitis in the Japanese population.…”

Use of immunoglobulins in the prevention of GvHD in a xenogeneic NOD/SCID/γc− mouse model

“…The role of IL-17-producing Thelper cells is increasingly being recognized in GvHD. [63][64][65][66][67] Tournadre et al 68 recently showed by analyzing muscle biopsies of patients with inflammatory myopathies that IVIG could mediate their immunomodulation by acting on the Th17 pathway. One could speculate that IVIG exert their modulatory effect on GvHD by impairing the Th17 pathway, although more analysis on other Th17-family cytokines and on the nature of IL-17 secreting cells in our model will be required to confirm this hypothesis.…”