RNAseq of lymphocyte populations in Graft vs Host Disease
Ontology highlight
ABSTRACT: In this experiment we harvested donor T cells from recipient allogeneic mice and examined changes in gene expression in FLICA (caspase-1 activation) positive and negative T cell populations
Project description:Graft-versus-host disease (GVHD) results from recognition of host antigens by donor T cells following allogeneic hematopoietic cell transplantion (AHCT). Notably, histoincompatibility between donor and recipient is necessary but not sufficient to elicit GVHD. Therefore, we tested the hypothesis that some donors may be “stronger alloresponders” than others, and consequently more likely to elicit GVHD. To this end, we analyzed the gene expression profile of CD4 and CD8 T cells from 50 AHCT donors. We found that pre-AHCT gene expression profiling segregates donors whose recipient suffered from GVHD or not. The “dangerous donor” trait (GVHD+ recipient) is under polygenic control and is shaped by the activity of genes that regulate diverse cell functions including TGF-β signaling and cell proliferation. We also performed gene expression profiling in T cells harvested from 40 AHCT recipients on day 365 post-AHCT. The donor gene profile defined on day 0 showed exceedingly strong correlation with that of recipient CD4 and CD8 T cells harvested one year post-AHCT. These data suggest that donor gene profiles linked with GVHD were largely imprinted at the hematopoietic stem cell level. The ability to discriminate strong and weak alloresponders using gene expression profiling could pave the way to personalized transplantation medicine. Keywords: comparative gene profile, cell type comparaison, GVHD+, GVHD-
Project description:Allogeneic T cell expansion is the primary determinant of graft-versus-host disease (GVHD), and current dogma dictates that this is driven by histocompatibility antigen disparities between donor and recipient. This paradigm represents a closed genetic system within which donor T cells interact with peptide-MHC complexes, though clonal interrogation remains challenging due to the sparseness of the T cell repertoire. We developed a Bayesian model using donor and recipient TCR frequencies in murine stem cell transplant systems to define limited common expansion of T cell clones across genetically identical donor-recipient pairs. A subset of donor CD4 T cell clonotypes differentially expanded in identical recipients and were microbiota dependent. Microbiota-specific T cells augmented GVHD lethality and could target microbial antigen presented by gastrointestinal epithelium during an alloreactive response. The microbiota thus serves as a source of cognate antigen that contributes to clonotypic T cell expansion and the induction of GVHD independent of donor-recipient genetics.
Project description:Lethally irradiated mice were transferred with bone marrow cells together with allogeneic Treg cells isolated from CD226+/+ TIGIT+/+, CD226-/- TIGIT+/+, CD226+/+ TIGIT-/-, or CD226-/- TIGIT-/- mice, followed by allogeneic wild-type Tconv cells two days later to induce acute GVHD. We performed scRNA sequencing of donor T cells isolated from the spleen of recipient mice eight days after GVHD induction.
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.
Project description:<p>Despite improvement in clinical management, allogeneic hematopoietic stem cell transplantation (HSCT) is still hampered by high morbidity and mortality rates, mainly due to Graft versus host disease (GvHD). Recently, it has been demonstrated that the allogeneic immune response might be influenced by external factors such as tissues microenvironment or host microbiota.</p><p>Here we used high throughput metabolomics (UPLC-MS/MS) in two cohorts of genotypically HLA-identical related recipient and donor pairs. A first monocentric cohort from Saint Louis hospital (Paris, France) was used as an exploratory cohort (n=43) and a second multicentric national cohort from Cryostem biobank was used as a confimatory cohort (n=56).</p><p>Metabolomic profile markedly differed between recipients and donors. At the onset of acute GvHD, in addition to host-derived metabolites, we identified significant variation in microbiota-derived metabolites, especially in Aryl hydrocarbon Receptor (AhR) ligands, bile acids and plasmalogens. Altogether, our findings support that the allogeneic immune response during acute GvHD might be influenced by bile acids and by the decreased production of AhR ligands by microbiota that could limit indoleamine 2,3-dioxygenase (IDO) induction and influence allogeneic T-cell reactivity.</p><p><br></p><p><a href='https://www.ebi.ac.uk/metabolights/editor/study/MTBLS204/descriptors' rel='noopener noreferrer' target='_blank'>MTBLS204</a> contains study information relating to cohort 1.</p><p><a href='https://www.ebi.ac.uk/metabolights/editor/study/MTBLS205/descriptors' rel='noopener noreferrer' target='_blank'>MTBLS205</a> contains study information relating to cohort 2.</p>
Project description:<p>Despite improvement in clinical management, allogeneic hematopoietic stem cell transplantation (HSCT) is still hampered by high morbidity and mortality rates, mainly due to Graft versus host disease (GvHD). Recently, it has been demonstrated that the allogeneic immune response might be influenced by external factors such as tissues microenvironment or host microbiota.</p><p>Here we used high throughput metabolomics (UPLC-MS/MS) in two cohorts of genotypically HLA-identical related recipient and donor pairs. A first monocentric cohort from Saint Louis hospital (Paris, France) was used as an exploratory cohort (n=43) and a second multicentric national cohort from Cryostem biobank was used as a confimatory cohort (n=56).</p><p>Metabolomic profile markedly differed between recipients and donors. At the onset of acute GvHD, in addition to host-derived metabolites, we identified significant variation in microbiota-derived metabolites, especially in Aryl hydrocarbon Receptor (AhR) ligands, bile acids and plasmalogens. Altogether, our findings support that the allogeneic immune response during acute GvHD might be influenced by bile acids and by the decreased production of AhR ligands by microbiota that could limit indoleamine 2,3-dioxygenase (IDO) induction and influence allogeneic T-cell reactivity.</p><p><br></p><p><a href='https://www.ebi.ac.uk/metabolights/editor/study/MTBLS204/descriptors' rel='noopener noreferrer' target='_blank'>MTBLS204</a> contains study information relating to cohort 1.</p><p><a href='https://www.ebi.ac.uk/metabolights/editor/study/MTBLS205/descriptors' rel='noopener noreferrer' target='_blank'>MTBLS205</a> contains study information relating to cohort 2.</p>
Project description:The goals of the study are to compare differenely expressed genes in allogeneic and syngeneic CD8+ T cells isolated from splenocytes of allogeneic (donor: C57BL/6, host: Balb/c) and syngeneic (donor: Balb/c, host: Balb/c) HSCT mice.
Project description:The goals of the study are to compare differently expressed genes in allogeneic and syngeneic CD4+ T cells isolated from splenocytes of allogeneic (donor: C57BL/6, host: Balb/c) and syngeneic (donor: Balb/c, host: Balb/c) HSCT mice.
Project description:The goals of the study are to compare differenely expressed genes in allogeneic and syngeneic CD3+ T cells isolated from splenocytes of allogeneic (donor: C57BL/6, host: Balb/c) and syngeneic (donor: Balb/c, host: Balb/c) HSCT mice.