Although the Th17 subset and its signature cytokine, interleukin (IL)-17A (IL-17), are implicated in certain autoimmune diseases, their role in cancer remains to be further explored. IL-17 has been shown to be elevated in several types of cancer, but how it might contribute to tumor growth is still unclear. We show that growth of B16 melanoma and MB49 bladder carcinoma is reduced in IL-17−/− mice but drastically accelerated in IFN-γ−/− mice, contributed to by elevated intratumoral IL-17, indicating a role of IL-17 in promoting tumor growth. Adoptive transfer studies and analysis of the tumor microenvironment suggest that CD4+ T cells are the predominant source of IL-17. Enhancement of tumor growth by IL-17 involves direct effects on tumor cells and tumor-associated stromal cells, which bear IL-17 receptors. IL-17 induces IL-6 production, which in turn activates oncogenic signal transducer and activator of transcription (Stat) 3, up-regulating prosurvival and proangiogenic genes. The Th17 response can thus promote tumor growth, in part via an IL-6–Stat3 pathway.

In acute graft-versus-host disease (GVHD), naive donor CD4

No abstract

Sorted CD4+ and CD8+ T cells from the peripheral blood or bone marrow of donor C57BL/6 (H-2b) mice were tested for their capacity to induce graft-versus-host disease (GVHD) by injecting the cells, along with stringently T cell–depleted donor marrow cells, into lethally irradiated BALB/c (H-2d) host mice. The peripheral blood T cells were at least 30 times more potent than the marrow T cells in inducing lethal GVHD. As NK1.1+ T cells represented <1% of all T cells in the blood and ∼30% of T cells in the marrow, the capacity of sorted marrow NK1.1− CD4+ and CD8+ T cells to induce GVHD was tested. The latter cells had markedly increased potency, and adding back marrow NK1.1+ T cells suppressed GVHD. The marrow NK1.1+ T cells secreted high levels of both interferon γ (IFN-γ) and interleukin 4 (IL-4), and the NK1.1− T cells secreted high levels of IFN-γ with little IL-4. Marrow NK1.1+ T cells obtained from IL-4−/− rather than wild-type C57BL/6 donors not only failed to prevent GVHD but actually increased its severity. Together, these results demonstrate that GVHD is reciprocally regulated by the NK1.1− and NK1.1+ T cell subsets via their differential production of cytokines.

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...