The binding activity of Mel‐18 at the <i>Il17a</i> promoter is regulated by the integrated signals of the TCR and polarizing cytokines

• The transcriptional networks controlling breakthrough acute GVHD can be mapped, and correlate closely with clinical disease.• Breakthrough acute GVHD is transcriptionally controlled by T-cell persistence, inflammation, and Th/Tc17 skewing.One of the central challenges of transplantation is the development of alloreactivity despite the use of multiagent immunoprophylaxis. Effective control of this immune suppression-resistant T-cell activation represents one of the key unmet needs in the fields of both solid-organ and hematopoietic stem cell transplant (HCT). To address this unmet need, we have used a highly translational nonhuman primate (NHP) model to interrogate the transcriptional signature of T cells during breakthrough acute graftversus-host disease (GVHD) that occurs in the setting of clinically relevant immune suppression and compared this to the hyperacute GVHD, which develops in unprophylaxed or suboptimally prophylaxed transplant recipients. Our results demonstrate the complex character of the alloreactivity that develops during ongoing immunoprophylaxis and identify 3 key transcriptional hallmarks of breakthrough acute GVHD that are not observed in hyperacute GVHD: (1) T-cell persistence rather than proliferation, (2) evidence for highly inflammatory transcriptional programming, and (3) skewing toward a T helper (Th)/T cytotoxic (Tc)17 transcriptional program. Importantly, the gene coexpression profiles from human HCT recipients who developed GVHD while on immunosuppressive prophylactic agents recapitulated the patterns observed in NHP, and demonstrated an evolution toward a more inflammatory signature as time posttransplant progressed. These results strongly implicate the evolution of both inflammatory and interleukin 17-based immune pathogenesis in GVHD, and provide the first map of this evolving process in primates in the setting of clinically relevant immunomodulation. This map represents a novel transcriptomic resource for further systems-based efforts to study the breakthrough alloresponse that occurs posttransplant despite immunoprophylaxis and to develop evidence-based strategies for effective treatment of this disease. (Blood. 2016;128(21):2568-2579

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“…15 The enrichment of Mel-18 targets was also important, given that Mel-18 has been observed to be a key component in Th17 cell programming. 16 …”

Section: Transcriptomics Distinguish Hyperacute and Breakthrough Acutmentioning

confidence: 99%

Systems analysis uncovers inflammatory Th/Tc17-driven modules during acute GVHD in monkey and human T cells

Furlan

Watkins

Tkachev

et al. 2016

Blood

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“…(2,41) Several studies point to an important role of Ezh2 and H3K27me3 in multiple lineages of effector T cells. (14,17,20,25) Genome-wide mapping analysis revealed that repressive H3K27me3 marked genes associated with differentiation and maintenance of effector and memory T cells. (1,51) Most recently, we have demonstrated new and essential roles of Ezh2 in regulating inflammatory T cell responses in mice after allogeneic BMT.…”

Section: Introductionmentioning

confidence: 99%

Ezh2 Regulates Transcriptional and Posttranslational Expression of T-bet and Promotes Th1 Cell Responses Mediating Aplastic Anemia in Mice

Tong

Xie

et al. 2014

The Journal of Immunology

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Acquired aplastic anemia (AA) is a potentially fatal bone marrow (BM) failure syndrome. IFN-γ-producing T helper (Th)1 CD4+ T cells mediate the immune destruction of hematopoietic cells, and are central to the pathogenesis. However, the molecular events that control the development of BM-destructive Th1 cells remain largely unknown. Ezh2 is a chromatin-modifying enzyme that regulates multiple cellular processes primarily by silencing gene expression. We recently reported that Ezh2 is crucial for inflammatory T cell responses after allogeneic BM transplantation. To elucidate whether Ezh2 mediates pathogenic Th1 responses in AA and the mechanism of Ezh2 action in regulating Th1 cells, we studied the effects of Ezh2 inhibition in CD4+ T cells using a mouse model of human AA. Conditionally deleting Ezh2 in mature T cells dramatically reduced the production of BM-destructive Th1 cells in vivo, decreased BM-infiltrating Th1 cells, and rescued mice from BM failure. Ezh2 inhibition resulted in significant decrease in the expression of Tbx21 and Stat4 (which encode transcription factors T-bet and STAT4, respectively). Introduction of T-bet but not STAT4 into Ezh2-deficient T cells fully rescued their differentiation into Th1 cells mediating AA. Ezh2 bound to the Tbx21 promoter in Th1 cells, and directly activated Tbx21 transcription. Unexpectedly, Ezh2 was also required to prevent proteasome-mediated degradation of T-bet protein in Th1 cells. Our results identify T-bet as the transcriptional and post-translational Ezh2 target that acts together to generate BM-destructive Th1 cells, and highlight the therapeutic potential of Ezh2 inhibition in reducing AA and other autoimmune diseases.

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“…However, whether genetic inactivation of Ezh2 leads to inappropriate differentiation of Th1 and Th2 has not been effectively tested. A recent study has shown that Ezh2 also positively correlated to the expression of IL17A and IL17F [90]. These studies pointed to a potential impact of Ezh2 and repressive H3K27me3 in multiple lineages of effector T cells.…”

Section: Function Of Histone Methyltransferases In Effector T Cellsmentioning

confidence: 91%

“…Some studies suggested that Ezh2 was correlated with Th1 and Th2 cell development [24,90,91]. Ezh2 bound to the IFNG promoter and proximal transcribed region both in Th1 and Th2 cells [91].…”

Section: Function Of Histone Methyltransferases In Effector T Cellsmentioning

confidence: 99%

Histone Methyltransferase and Histone Methylation in Inflammatory T-Cell Responses

Tong

Bishop

et al. 2013

Immunotherapy

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During immune responses, T cells require tightly controlled expression of transcriptional programs to regulate the balance between beneficial and harmful immunity. These transcriptional programs are critical for the lineage specification of effector T cells, the production of effector cytokines and molecules, and the development and maintenance of memory T cells. An emerging theme is that post-translational modification of histones by methylation plays an important role in orchestrating the expression of transcriptional programs in T cells. In this article, we provide a broad overview of histone methylation signatures for effector molecules and transcription factors in T cells, and the functional importance of histone methyltransferases in regulating T-cell immune responses.

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The binding activity of Mel‐18 at the Il17a promoter is regulated by the integrated signals of the TCR and polarizing cytokines

Cited by 13 publications

References 81 publications

Systems analysis uncovers inflammatory Th/Tc17-driven modules during acute GVHD in monkey and human T cells

Systems analysis uncovers inflammatory Th/Tc17-driven modules during acute GVHD in monkey and human T cells

Ezh2 Regulates Transcriptional and Posttranslational Expression of T-bet and Promotes Th1 Cell Responses Mediating Aplastic Anemia in Mice

Histone Methyltransferase and Histone Methylation in Inflammatory T-Cell Responses

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