Similar Datasets
Project description:Granzyme A-producing CD4+ T cells in graft-versus-host disease
| PRJNA646973 | ENA
Project description:Acute graft-versus-host disease (aGVHD) can occur after hematopoietic cell transplant in patients undergoing treatment for hematological malignancies or inborn errors. Although CD4+ T helper (Th) cells play a major role in aGVHD, the mechanisms by which they contribute, particularly within the intestines, have remained elusive. We have identified a potentially novel subset of Th cells that accumulated in the intestines and produced the serine protease granzyme A (GrA). GrA+ Th cells were distinct from other Th lineages and exhibited a noncytolytic phenotype. In vitro, GrA+ Th cells differentiated in the presence of IL-4, IL-6, and IL-21 and were transcriptionally unique from cells cultured with either IL-4 or the IL-6/IL-21 combination alone. In vivo, both STAT3 and STAT6 were required for GrA+ Th cell differentiation and played roles in maintenance of the lineage identity. Importantly, GrA+ Th cells promoted aGVHD-associated morbidity and mortality and contributed to crypt destruction within intestines but were not required for the beneficial graft-versus-leukemia effect. Our data indicate that GrA+ Th cells represent a distinct Th subset and are critical mediators of aGVHD.
| S-EPMC7526544 | biostudies-literature
Project description:Granzyme B (GzmB) has previously been shown to be critical for CD8(+) T cell-mediated graft-versus-host disease (GVHD) but dispensable for GVHD mediated by CD4(+) T cells. However, previous studies used high doses of CD4(+) T cells in MHC-mismatched models that caused rapid and lethal GVHD. Because of the hyperacute lethality, it is possible that the role of GzmB was concealed by the system. Therefore, in this study, we have titrated down the T cell dose to precisely determine the contribution of GzmB in GVHD mediated by CD4(+)CD25(-) T cells. Surprisingly, we have found that GzmB(-/-)CD4(+)CD25(-) T cells cause more severe GVHD compared with wild-type CD4(+)CD25(-) T cells in both MHC-matched and mismatched models. Mechanistic analyses reveal that although GzmB does not affect donor T cell engraftment, proliferation or tissue-specific migration, GzmB(-/-) CD4(+)CD25(-) T cells exhibit significantly enhanced expansion because of GzmB-mediated activation-induced cell death of wild-type CD4(+)CD25(-) T cells. As a result of enhanced expansion, GzmB(-/-) T cells produced higher amounts of proinflammatory cytokines (e.g., TNF-α and IFN-γ) that may contribute to the exacerbated GVHD. These results reveal that GzmB diminishes the ability of CD4(+) T cells to cause acute GVHD, which contradicts its established role in CD8(+) T cells. The differential roles suggest that targeting GzmB in selected T cell subsets may provide a strategy to control GVHD.
| S-EPMC4610854 | biostudies-literature
Project description:Despite increasing evidence for a protective role of invariant (i) NKT cells in the control of graft-versus-host disease (GVHD), the mechanisms underpinning regulation of the allogeneic immune response in humans are not known. In this study, we evaluated the distinct effects of human in vitro expanded and flow-sorted human CD4+ and CD4- iNKT subsets on human T cell activation in a pre-clinical humanized NSG mouse model of xenogeneic GVHD. We demonstrate that human CD4- but not CD4+ iNKT cells could control xenogeneic GVHD, allowing significantly prolonged overall survival and reduced pathological GVHD scores without impairing human T cell engraftment. Human CD4- iNKT cells reduced the activation of human T cells and their Th1 and Th17 differentiation in vivo. CD4- and CD4+ iNKT cells had distinct effects upon DC maturation and survival. Compared to their CD4+ counterparts, in co-culture experiments in vitro, human CD4- iNKT cells had a higher ability to make contacts and degranulate in the presence of mouse bone marrow-derived DCs, inducing their apoptosis. In vivo we observed that infusion of PBMC and CD4- iNKT cells was associated with decreased numbers of splenic mouse CD11c+ DCs. Similar differential effects of the iNKT cell subsets were observed on the maturation and in the induction of apoptosis of human monocyte-derived dendritic cells in vitro. These results highlight the increased immunosuppressive functions of CD4- versus CD4+ human iNKT cells in the context of alloreactivity, and provide a rationale for CD4- iNKT selective expansion or transfer to prevent GVHD in clinical trials.
| S-EPMC6204997 | biostudies-literature
Project description:Analysis of donor CD4+ and CD8+ T cells purified from spleens and ovaries after murine syngeneic and allogeneic hematopoietic stem cell transplantation Infertility associated with ovarian failure is a serious late complication for female survivors of allogeneic hematopoietic stem cell transplantation (SCT). While the role of pretransplant conditioning regimen has been well appreciated, increasing application of reduced-intensity conditioning facilitated us to revisit the other factors possibly affecting ovarian function after allogeneic SCT. We have addressed whether donor T-cell mediated graft-versus-host disease (GVHD) could be causally related to female infertility in mice. To study transcriptomes of donor T cells infiltrating into the ovary, donor T cells were sorted from recipients' ovaries and microarray analysis was performed.
2017-05-12 | GSE81397 | GEO
Project description:In our previous work we could identify defects in human regulatory T cells (Tregs) likely favoring the development of graft-versus-host disease (GvHD) following allogeneic stem cell transplantation (SCT). Treg transcriptome analyses comparing GvHD and immune tolerant patients uncovered regulated gene transcripts highly relevant for Treg cell function. Moreover, granzyme A (GZMA) also showed a significant lower expression at the protein level in Tregs of GvHD patients. GZMA induces cytolysis in a perforin-dependent, FAS-FASL independent manner and represents a cell-contact dependent mechanism for Tregs to control immune responses. We therefore analyzed the functional role of GZMA in a murine standard model for GvHD. For this purpose, adoptively transferred CD4+CD25+ Tregs from gzmA-/- mice were analyzed in comparison to their wild type counterparts for their capability to prevent murine GvHD. GzmA-/- Tregs home efficiently to secondary lymphoid organs and do not show phenotypic alterations with respect to activation and migration properties to inflammatory sites. Whereas gzmA-/- Tregs are highly suppressive in vitro, Tregs require GZMA to rescue hosts from murine GvHD, especially regarding gastrointestinal target organ damage. We herewith identify GZMA as critical effector molecule of human Treg function for gastrointestinal immune response in an experimental GvHD model.
| S-EPMC4415808 | biostudies-literature
Project description:Knockout of MHC class II on Ccl19 expressing fibroblastic reticular cells results in the hyper-activation of allogenic CD4+ T cells in the effoctor phase of aGvHD, due to the dyregulation of regulatory T cells (Tregs).
2021-03-03 | GSE168114 | GEO
Project description:Dermatologists are ideally suited to manage the various cutaneous sequelae of graft-versus-host disease (GVHD) outlined in part I of this review. However, the complexity of the patient with GVHD, including comorbidities, potential drug interactions related to polypharmacy, and the lack of evidence-based treatment guidelines, are significant challenges to optimizing patient care. In this section, we will provide an outline for the role of the dermatologist in a multispecialty approach to caring for patients with GVHD.
| S-EPMC7357210 | biostudies-literature
Project description:The role of IL-17 and IL-17-producing CD4+ T cells in acute graft-versus-host disease (GVHD) has been controversial in recent mouse and human studies. We carried out studies in a murine acute GVHD model of fully major histocompatibility complex-mismatched myeloablative bone marrow transplantation. We showed that donor wild-type CD4+ T cells exacerbated acute GVHD compared with IL-17-/- CD4+ T cells, while IL-17 reduced the severity of acute GVHD. The augmentation of acute GVHD by transferred donor IL-17-producing CD4+ T cells was associated with increased Th1 responses, while IL-17 decreased the percentages of Th1 cells in the GVHD target organs. Furthermore, IL-17 reduced the infiltration of macrophages into the GVHD tissues. In vitro study showed that IL-17 could downregulate Th1 responses, possibly through inhibiting IL-12 production by donor macrophages. Depletion of macrophages in vivo diminished the protective effect of IL-17. Our results demonstrated the differential roles of adoptively transferred donor IL-17-producing CD4+ T cells and IL-17 in the same acute GVHD model.
| S-EPMC5843609 | biostudies-literature
Project description:Damage to the gastrointestinal tract is a major cause of morbidity and mortality in graft-versus-host disease (GVHD) and is attributable to T cell-mediated inflammation. In this work, we identified a unique CD4+ T cell population that constitutively expresses the ?2 integrin CD11c and displays a biased central memory phenotype and memory T cell transcriptional profile, innate-like properties, and increased expression of the gut-homing molecules ?4?7 and CCR9. Using several complementary murine GVHD models, we determined that adoptive transfer and early accumulation of ?2 integrin-expressing CD4+ T cells in the gastrointestinal tract initiated Th1-mediated proinflammatory cytokine production, augmented pathological damage in the colon, and increased mortality. The pathogenic effect of this CD4+ T cell population critically depended on coexpression of the IL-23 receptor, which was required for maximal inflammatory effects. Non-Foxp3-expressing CD4+ T cells produced IL-10, which regulated colonic inflammation and attenuated lethality in the absence of functional CD4+Foxp3+ T cells. Thus, the coordinate expression of CD11c and the IL-23 receptor defines an IL-10-regulated, colitogenic memory CD4+ T cell subset that is poised to initiate inflammation when there is loss of tolerance and breakdown of mucosal barriers.
| S-EPMC5004941 | biostudies-literature