Tc17 cells are a proinflammatory, plastic lineage of pathogenic CD8+ T cells that induce GVHD without antileukemic effects

Gartlan, Kate H.; Markey, Kate A.; Varelias, Antiopi; Bunting, Mark; Koyama, Motoko; Kuns, Rachel D.; Raffelt, Neil C.; Olver, Stuart D.; Lineburg, Katie E.; Cheong, Melody; Teal, Bianca E.; Lor, Mary; Comerford, Iain; Teng, Michele W.L.; Smyth, Mark J.; McCluskey, James; Rossjohn, Jamie; Stockinger, Brigitta; Boyle, Glen M.; Lane, Steven; Clouston, Andrew D.; McColl, Shaun R.; MacDonald, Kelli P. A.; Hill, Geoffrey R.

doi:10.1182/blood-2015-01-622662

Cited by 112 publications

(130 citation statements)

References 60 publications

Supporting

Mentioning

120

Contrasting

Order By: Relevance

“…35 As shown in Figure 5D, significant overlap existed between the genes identified in mice and the NHP breakthrough acute GVHD transcriptome. Thus, of 25 Tc17 genes identified in murine GVHD, 35 21 were identified as concordantly differentially expressed in either the breakthrough acute vs autologous control or the breakthrough acute vs healthy control comparison. Three were not concordant and 1 gene (Ly6c1) has no human/NHP For personal use only.…”

Section: -21mentioning

confidence: 91%

“…Red points denote pivot transcripts, whose expression meets cutoffs noted above, and whose differential expression in breakthrough acute and hyperacute samples compared with healthy controls are in opposite directions. (D) Heatmap showing the expression levels of inflammatory Tc17-related genes identified in a study of fate-mapped murine Tc17 cells 35 in the NHP breakthrough acute GVHD arrays compared with either autologous controls (Auto, left column) or healthy controls (HC, right column). The rows in the heatmap contain 24 genes previously identified as overrepresented (n 5 12, top half of heatmap) and underrepresented (n 5 12, bottom half of heatmap) in murine Tc17 cells during GVHD relative to controls.…”

Section: -21mentioning

confidence: 99%

See 1 more Smart Citation

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

Furlan

Watkins

Tkachev

et al. 2016

Blood

View full text Add to dashboard Cite

• 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

show abstract

Section: -21mentioning

confidence: 91%

Section: -21mentioning

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

View full text Add to dashboard Cite

show abstract

“…[1][2][3][4]38,39 In nontransplant settings, Th17 have in turn been described as protective in response to fungal infections and other pathogens, 40 pathogenic in multiple human autoimmune diseases, 41 and regulatory during inflammation resolution. 13 This heterogeneity in Th17 function has been attributed to their high degree of plasticity such that Th17 have been reported to transdifferentiate between these functional roles.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4][5][6] Plasticity has been widely reported in CD4 IL-17A 1 (Tc17) T cells in a range of infectious and autoimmune settings. [6][7][8][9][10][11][12] We have recently described Tc17 cytokine plasticity in murine allo-SCT recipients, 1 which is characteristic of a hyper-proinflammatory T-cell subset that contributes to GVHD but fails to mediate graft-versus-leukemia effects. 1,3 Th17 cells have been reported to transdifferentiate toward highly functional distinct phenotypes, including the acquisition of regulatory and follicular B-cell helper function (Tfh).…”

Section: Introductionmentioning

confidence: 99%

“…[6][7][8][9][10][11][12] We have recently described Tc17 cytokine plasticity in murine allo-SCT recipients, 1 which is characteristic of a hyper-proinflammatory T-cell subset that contributes to GVHD but fails to mediate graft-versus-leukemia effects. 1,3 Th17 cells have been reported to transdifferentiate toward highly functional distinct phenotypes, including the acquisition of regulatory and follicular B-cell helper function (Tfh). [13][14][15] In addition, multiple studies of autoimmunity have described differential pathogenic capacity within Th17 subsets due to cytokine plasticity correlating with the acquisition of "Th1-like" phenotypes.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Th17 plasticity and transition toward a pathogenic cytokine signature are regulated by cyclosporine after allogeneic SCT

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

Clinical and Molecular Phenotyping in Scleromyxedema Pretreatment and Posttreatment With Intravenous Immunoglobulin

Mecoli

Talbot

Fava

et al. 2020

Arthritis Care & Research

View full text Add to dashboard Cite

Objective. Scleromyxedema (SMX) is a rare systemic sclerosis mimic that often responds to intravenous immunoglobulin (IVIG) therapy, yet the resulting clinical and biochemical changes have not been well characterized. To better understand the pathogenesis of the disease and the efficacy of IVIG, we sought to explore whether IVIG would introduce a measurable biologic effect corresponding with clinical improvement.Methods. Fifteen patients with SMX were recruited for the study. Clinical information and peripheral blood mononuclear cells for flow cytometry were obtained immediately before and again 1-2 weeks after patients received IVIG therapy. Ten patients also underwent skin biopsies for gene expression analysis both before and after IVIG therapy. Clinical data included measures of skin involvement (modification of the modified Rodnan skin thickness score [MMRSS] and percentage of body surface area) and several patient-reported outcome measures assessing patients' skin.Results. Posttreatment, the average MMRSS score decreased from mean ± SD 13.6 ± 2.6 to 10.3 ± 1.9; P = 0.003. There were also significant improvements in skin flexibility (mean ± SD 5.4 ± 0.8 to 3.2 ± 0.7; P = 0.003) and softening (mean ± SD 4.9 ± 0.9 to 2.6 ± 0.6; P = 0.022). Baseline levels of Tc17 cells (CD8+CCR6+CXCR3+CCR4-) correlated with the extent of skin involvement as measured by MMRSS pretreatment (r = 0.69, P = 0.012) and decreased after IVIG therapy (mean ± SD 3.4% ± 3.2% to 1.3% ± 1.7%; P = 0.008). Posttreatment analysis of RNA in skin tissue revealed a decrease in gene expression of transforming growth factor β (TGFβ) cytokines as well as several interferon-inducible proteins.Conclusion. This open-label study further supports the evidence that patients with SMX respond both objectively and subjectively to IVIG therapy. Biologic studies suggest a role for T lymphocytes in the pathogenesis of the disease and reveal the potential significance of TGFβ and interferon pathways.

show abstract

Tc17 cells are a proinflammatory, plastic lineage of pathogenic CD8+ T cells that induce GVHD without antileukemic effects

Abstract: Key Points Donor-derived Tc17 cells differentiate early after allogeneic transplant in response to IL-6 and alloantigen presentation by host DCs. Tc17 are highly proinflammatory and pathogenic posttransplant, but exert limited or no GVL activity.

Cited by 112 publications

References 60 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

Th17 plasticity and transition toward a pathogenic cytokine signature are regulated by cyclosporine after allogeneic SCT

Clinical and Molecular Phenotyping in Scleromyxedema Pretreatment and Posttreatment With Intravenous Immunoglobulin

Contact Info

Product

Resources

About