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Antigen-specific type 1 regulatory T cells have a distinct molecular identity and suppress through CTLA-4 and PD-1

ABSTRACT: We report the bulk-cell-based TCR sequences profiling from high-throughput sequencing of human healthy T-allo10 cells. The T-allo10 cell product is consistently enriched for Tr1 cells, is specifically anergic, and suppresses alloantigen-responsive Teff cells. Analysis of Tr1 cells from the T-allo10 product showed that the both TCRa and TCRb repertoires are highly skewed towards dominant clones and has diverged from the parental CD4+ T cells used to generate the T-allo10 product, non-Tr1 cells from the same T-allo10 product, and Teff cells from the control T-allo product. The data indicate that T-allo10-derived Tr1 cells, but not non-Tr1 cells, undergo clonal expansion in response to the alloantigen stimulation, suggesting that the Tr1 cells are the antigen specific component of the T-allo10 cell product. T-allo10 cells are currently undergoing clinical evaluation for safety in a phase I clinical trial (ClinicalTrials.gov ID: NCT03198234).

ORGANISM(S): Homo sapiens

PROVIDER: GSE160274 | GEO | 2021/10/27

REPOSITORIES: GEO

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Project description:Regulatory T cells restore tolerance in preclinical models of immune-mediated diseases and are therefore a promising alternative to conventional immune-suppression for preventing graft-versus-host disease (GvHD) in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Adaptive CD4+ Type 1 regulatory T (Tr1) cells specific for alloantigens are induced in vitro by interleukin-10 (IL-10). Therefore, we evaluated whether infusion of Tr1 cells could promote immune-competence to foreign antigens and long-term alloantigen-specific tolerance. In this phase 1-2 trial, we performed adoptive transfer with IL-10-induced alloantigen-specific Tr1 cells (IL-10-DLI), without immune-suppression, in patients with high-risk hematopoietic malignancies transplanted with CD34+ cells from haploidentical donors. Donor T cells, primed ex vivo with host antigen-presenting-cells and IL-10, are anergic towards host-HLA antigens and contain host-specific Tr1 cells but also memory T cells able to respond to pathogens. Nineteen patients were enrolled in the trial. Twelve received IL-10-DLI. Seven were not evaluable because of early death/relapse, whereas five immune-reconstituted (>100/Âµl CD3+ T cells) at median day 28 after IL-10-DLI. T-cell counts and function progressively normalized in patients who received 105 CD3+ T cells/kg, whereas a higher dose (3x105 CD3+ T cells/kg) caused acute grade III GvHD in one patient. Four patients are alive, in disease remission and immune-suppression-free at a median follow-up of 3.3 years, three of them were analyzed by microarrays; their T-cell receptor repertoire and gene expression profiles are comparable to those of healthy subjects. Cell therapy with IL-10-DLI is feasible, safe, and provides immune-competence. This trial is the first step towards widespread use of Tr1 cells as adjuvant treatment in allogeneic HSCT (IS/11/6172/8309/8391). Keywords: classification of clinical samples Whole blood samples of three healthy donors and three different patients collected at various time points after hematopoietic stem cell transplantation (HSCT) before and after the subsequent administration of IL-10 anergized T cells were analysed on a custom Agilent 8x15K 60mer oligonucleotide microarray encomprising 4610 probes in triplicates. The microarray is dedicated to transplantation research and was designed based on current literature and published and unpublished data provided by the RISET consortium. For the probe selection procedure we specially focused on the detection of multiple transcript variants of a gene, on optimized hybridization properties of the probes, and on the avoidance of crosshybridization. The RISET 1.0 platform (GPL10370) is a precursor of the RISET 2.0 microarray (GPL8136).

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Antigen-specific type 1 regulatory T cells have a distinct molecular identity and suppress through CTLA-4 and PD-1

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