Clonal dynamics of alloreactive T cells in kidney allograft rejection after anti-PD-1 therapy [bulkTCRseq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE216758 | GEO | 2023/02/01
REPOSITORIES: GEO
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Project description:Kidney transplant recipients are at particular risk for developing tumors, many of which are now routinely treated with immune checkpoint inhibitors (ICIs); however, ICI therapy can precipitate transplant rejection. We utilized TCR sequencing to identify and track alloreactive T cells in a patient with melanoma who experienced kidney transplant rejection following ICI therapy. ICI therapy was associated with a sharp increase in circulating alloreactive CD8+ T cell clones, many of which were also detected in the rejected kidney but not at tumor sites. Longitudinal and cross-tissue TCR analyses revealed unintended expansion of alloreactive CD8+ T cells induced by ICI therapy for cancer, coinciding with ICI-associated organ rejection.
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Project description:Kidney transplant recipients are at particular risk for developing tumors, many of which are now routinely treated with immune checkpoint inhibitors (ICIs); however, ICI therapy can precipitate transplant rejection. We utilized TCR sequencing to identify and track alloreactive T cells in a patient with melanoma who experienced kidney transplant rejection following ICI therapy. ICI therapy was associated with a sharp increase in circulating alloreactive CD8+ T cell clones, many of which were also detected in the rejected kidney but not at tumor sites. Longitudinal and cross-tissue TCR analyses revealed unintended expansion of alloreactive CD8+ T cells induced by ICI therapy for cancer, coinciding with ICI-associated organ rejection.
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Project description:The extent to which tissue-resident memory T (TRM) cells in transplanted organs possess alloreactivity is uncertain. This study investigates the alloreactive potential of TRM cells in kidney explants from four patients who experienced severe acute rejection leading to graft loss. Alloreactive T-cell receptors (TCRs) clones were identified in pre-transplant blood samples through mixed lymphocyte reactions, followed by single-cell RNA and TCR sequencing of the proliferated recipient T cells. Subsequently, these TCR clones were traced in the TRM cells of kidney explants, which were also subjected to single-cell RNA and TCR sequencing. The proportion of TRM cells expressing an alloreactive TCR in the four kidney explants varied from 0% to 9%. Notably, these alloreactive TCRs were predominantly found among CD4+ and CD8+ TRM cells with an effector phenotype. Intriguingly, alloreactive clones were present not only in recipient-derived TRM cells but also in donor-derived TRM cells, constituting up to 4% of the donor population, suggesting the presence of self-reactive TRM cells. Overall, our study demonstrates that T cells with alloreactive potential present in the peripheral blood prior to transplantation can infiltrate the kidney transplant and adopt a TRM phenotype.
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Project description:Adoptive natural regulatory T cell (nTreg) therapy has improved the outcome for patients suffering from graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (allo-HCT). However, fear of broad immune suppression and subsequent dampening of beneficial graft-versus-leukemic (GVL) responses remains a challenge. To address this concern, we generated alloreactive induced Tregs (iTregs) from resting CD4 or CD8 T cells and tested their ability to suppress GVH and maintain GVL responses. We utilized major mismatched and haploidentical murine models of HCT with host-derived lymphoma or leukemia cell lines to evaluate GVH and GVL responses simultaneously. Alloreactive CD4 iTregs were effective in preventing GVHD, but abrogated the GVL effect against aggressive leukemia. Alloreactive CD8 iTregs moderately attenuated GVHD while sparing the GVL effect. Hence, we reasoned that using a combination of CD4 and CD8 iTregs could achieve the optimal goal of allo-HCT. Indeed, the combinational therapy was superior to CD4 or CD8 iTreg singular therapy in GVHD control; importantly, the combinational therapy maintained GVL responses. Cellular analysis uncovered potent suppression of both CD4 and CD8 effector T cells by the combinational therapy that resulted in effective prevention of GVHD, which could not be achieved by either singular therapy. Gene expression profiles revealed alloreactive CD8 iTregs possess elevated expression of multiple cytolytic molecules compared to CD4 iTregs, which likely contributes to GVL preservation. Our study uncovers unique differences between alloreactive CD4 and CD8 iTregs that can be harnessed to create an optimal iTreg therapy for GVHD prevention with maintained GVL responses.
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Project description:A prospective study for investigating the T-cell receptor (TCR) repertoire in T-cell mediated rejection (TCMR) after kidney transplantation. The pre-formed donor-reactive TCR repertoire was tracked in blood and tissue of patients after kidney transplantation and characteristics of TCR repertoires from patients experiencing a rejection were compared to patients with no histopathological signs of rejection.
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Project description:Comparison of a cyclosporine-resistant murine CD8 T cell clone to a cyclosporine-sensitive murine T cell clone during activation (CSA = Cyclosporine A) Chronic allograft rejection is the leading cause of morbidity/mortality in solid organ and bone marrow transplant patients. It occurs in the setting of potent calcineurin and mTOR inhibitor therapies, implying that T cells mediating chronic rejection can function with compromised calcineurin-NFAT or IL-2 receptor signaling pathways. In murine models the T cells mediating allograft rejection in the setting of calcineurin inhibitor therapy are CD8 T cells making IFN-gamma without a requirement for perforin. It is not known whether these pathologic T cells are a unique subset or how they function. In parallel other animal model research has shown that alloepthelial cells residing in the donor organ are critical targets for rejection. While investigating T cell-alloepithelial cell interactions, we discovered an unusual alloreactive CD8 T cell population that recognized MHC class II I-Abm12. A CD8 T cell clone derived from that population was intrinsically-resistant to cyclosporine and rapamycin without prior exposure to either in vivo or in vitro. Microarray analysis comparing the novel CD8 T cell clone to a conventional CD8 CTL clone specific for MHC class I Kbm1 suggested that the TCR signaling pathway responsible for cyclosporine-resistance utilized the Aryl Hydrocarbon Receptor (AHR).
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Project description:We analyzed the T-cell receptor (TCR) repertoires from ten kidney transplant recipients. Five out of the ten kidney transplant recipients received ATLG while the other five recipients received basiliximab as induction therapy. TCR repertoires of CD4+ and CD8+ positive T-cells were assessed prior to transplantation and within the first month after transplantation as well as at three- and 12-months post-transplant. In addition, the pre-formed alloreactive TCR repertoire for each kidney transplant recipient was identified using mixed lymphocyte reaction and donor reactive T-cells were subjected to TCR beta sequencing. This dataset comprises a total of 106 samples. NGS TCR beta libraries of all samples were sequenced on an Illumina NextSeq 500 and raw sequencing data (in the form of fastq files) as well assembled clonotypes and their counts (in the form of clonotype tables) are provided.
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Project description:While direct allorecognition underpins both solid organ allograft rejection and tolerance induction, the specific molecular targets of most directly-alloreactive CD8+ T cells have not been defined. In this study, we used a combination of genetically-engineered MHC I constructs, mice with a hepatocyte-specific mutation in the class I antigen-presentation pathway and immunopeptidomic analysis to provide definitive evidence for the contribution of the peptide cargo of allogeneic MHC I molecules to transplant tolerance induction. We established a systematic approach for the discovery of directly-recognised pMHC epitopes, and identified 17 strongly immunogenic H-2Kb-associated peptides recognised by CD8+ T cells from B10.BR (H-2k) mice, 13 of which were also recognised by BALB/c (H-2d) mice. As few as five different tetramers used together were able to identify almost 40% of alloreactive T cells within a polyclonal population. To our knowledge, this represents the first example of such an approach in the context of direct allorecognition.
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