PMID- 34705520
OWN - NLM
STAT- MEDLINE
DCOM- 20211101
LR  - 20220910
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Print)
IS  - 1946-6234 (Linking)
VI  - 13
IP  - 617
DP  - 2021 Oct 27
TI  - Alloantigen-specific type 1 regulatory T cells suppress through CTLA-4 and PD-1 
      pathways and persist long-term in patients.
PG  - eabf5264
LID - 10.1126/scitranslmed.abf5264 [doi]
AB  - Type 1 regulatory T (Tr1) cells are inducible, interleukin (IL)-10(+)FOXP3(-) 
      regulatory T cells that can suppress graft-versus-host disease (GvHD) after 
      allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have optimized 
      an in vitro protocol to generate a Tr1-enriched cell product called T-allo10, 
      which is undergoing clinical evaluation in patients with hematological 
      malignancies receiving a human leukocyte antigen (HLA)-mismatched allo-HSCT. 
      Donor-derived T-allo10 cells are specific for host alloantigens, are anergic, and 
      mediate alloantigen-specific suppression. In this study, we determined the 
      mechanism of action of T-allo10 cells and evaluated survival of adoptively 
      transferred Tr1 cells in patients. We showed that Tr1 cells, in contrast to the 
      non-Tr1 population, displayed a restricted T cell receptor (TCR) repertoire, 
      indicating alloantigen-induced clonal expansion. Tr1 cells also had a distinct 
      transcriptome, including high expression of cytotoxic T lymphocyte-associated 
      protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). Blockade of CTLA-4 
      or PD-1/PD-L1 abrogated T-allo10-mediated suppression, confirming that these 
      proteins, in addition to IL-10, play key roles in Tr1-suppressive function and 
      that Tr1 cells represent the active component of the T-allo10 product. 
      Furthermore, T-allo10-derived Tr1 cells were detectable in the peripheral blood 
      of HSCT patients up to 1 year after T-allo10 transfer. Collectively, we revealed 
      a distinct molecular phenotype, mechanisms of action, and in vivo persistence of 
      alloantigen-specific Tr1 cells. These results further characterize Tr1 cell 
      biology and provide essential knowledge for the design and tracking of Tr1-based 
      cell therapies.
FAU - Chen, Pauline P
AU  - Chen PP
AUID- ORCID: 0000-0002-4730-3370
AD  - Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative 
      Medicine, Department of Pediatrics, Stanford University School of Medicine, 
      Stanford, CA 94305, USA.
FAU - Cepika, Alma-Martina
AU  - Cepika AM
AUID- ORCID: 0000-0003-2862-1901
AD  - Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative 
      Medicine, Department of Pediatrics, Stanford University School of Medicine, 
      Stanford, CA 94305, USA.
FAU - Agarwal-Hashmi, Rajni
AU  - Agarwal-Hashmi R
AUID- ORCID: 0000-0002-3865-8866
AD  - Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative 
      Medicine, Department of Pediatrics, Stanford University School of Medicine, 
      Stanford, CA 94305, USA.
FAU - Saini, Gopin
AU  - Saini G
AUID- ORCID: 0000-0001-7842-1241
AD  - Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative 
      Medicine, Department of Pediatrics, Stanford University School of Medicine, 
      Stanford, CA 94305, USA.
AD  - Center for Definitive and Curative Medicine, Stanford University School of 
      Medicine, Stanford, CA 94305, USA.
FAU - Uyeda, Molly J
AU  - Uyeda MJ
AD  - Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative 
      Medicine, Department of Pediatrics, Stanford University School of Medicine, 
      Stanford, CA 94305, USA.
AD  - Institute for Stem Cell Biology and Regenerative Medicine, Stanford University 
      School of Medicine, Stanford, CA 94305, USA.
FAU - Louis, David M
AU  - Louis DM
AUID- ORCID: 0000-0002-6845-5437
AD  - Institute for Immunity, Transplantation, and Infection, Stanford University 
      School of Medicine, Stanford, CA 94305, USA.
FAU - Cieniewicz, Brandon
AU  - Cieniewicz B
AUID- ORCID: 0000-0003-3268-7444
AD  - Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative 
      Medicine, Department of Pediatrics, Stanford University School of Medicine, 
      Stanford, CA 94305, USA.
FAU - Narula, Mansi
AU  - Narula M
AD  - Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative 
      Medicine, Department of Pediatrics, Stanford University School of Medicine, 
      Stanford, CA 94305, USA.
FAU - Amaya Hernandez, Laura C
AU  - Amaya Hernandez LC
AUID- ORCID: 0000-0002-8742-9111
AD  - Institute for Stem Cell Biology and Regenerative Medicine, Stanford University 
      School of Medicine, Stanford, CA 94305, USA.
FAU - Harre, Nicholas
AU  - Harre N
AUID- ORCID: 0000-0002-5377-9105
AD  - Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative 
      Medicine, Department of Pediatrics, Stanford University School of Medicine, 
      Stanford, CA 94305, USA.
FAU - Xu, Liwen
AU  - Xu L
AD  - Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative 
      Medicine, Department of Pediatrics, Stanford University School of Medicine, 
      Stanford, CA 94305, USA.
AD  - Division of Blood and Marrow Transplantation, Department of Medicine, Stanford 
      University School of Medicine, Stanford, CA 94305, USA.
AD  - Stanford Functional Genomics Facility, Stanford University School of Medicine, 
      Stanford, CA 94305, USA.
FAU - Thomas, Benjamin Craig
AU  - Thomas BC
AD  - Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative 
      Medicine, Department of Pediatrics, Stanford University School of Medicine, 
      Stanford, CA 94305, USA.
FAU - Ji, Xuhuai
AU  - Ji X
AUID- ORCID: 0000-0002-1768-6403
AD  - Stanford Functional Genomics Facility, Stanford University School of Medicine, 
      Stanford, CA 94305, USA.
FAU - Shiraz, Parveen
AU  - Shiraz P
AUID- ORCID: 0000-0002-6721-0358
AD  - Division of Blood and Marrow Transplantation, Department of Medicine, Stanford 
      University School of Medicine, Stanford, CA 94305, USA.
FAU - Tate, Keri M
AU  - Tate KM
AUID- ORCID: 0000-0001-8165-5049
AD  - Stanford Laboratory for Cell and Gene Medicine, Stanford University School of 
      Medicine, Stanford, CA 94305, USA.
FAU - Margittai, Dana
AU  - Margittai D
AUID- ORCID: 0000-0003-2992-5931
AD  - Stanford Laboratory for Cell and Gene Medicine, Stanford University School of 
      Medicine, Stanford, CA 94305, USA.
FAU - Bhatia, Neehar
AU  - Bhatia N
AUID- ORCID: 0000-0002-9829-1453
AD  - Stanford Laboratory for Cell and Gene Medicine, Stanford University School of 
      Medicine, Stanford, CA 94305, USA.
FAU - Meyer, Everett
AU  - Meyer E
AUID- ORCID: 0000-0001-7953-853X
AD  - Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative 
      Medicine, Department of Pediatrics, Stanford University School of Medicine, 
      Stanford, CA 94305, USA.
AD  - Division of Blood and Marrow Transplantation, Department of Medicine, Stanford 
      University School of Medicine, Stanford, CA 94305, USA.
FAU - Bertaina, Alice
AU  - Bertaina A
AUID- ORCID: 0000-0002-3729-436X
AD  - Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative 
      Medicine, Department of Pediatrics, Stanford University School of Medicine, 
      Stanford, CA 94305, USA.
AD  - Center for Definitive and Curative Medicine, Stanford University School of 
      Medicine, Stanford, CA 94305, USA.
FAU - Davis, Mark M
AU  - Davis MM
AUID- ORCID: 0000-0001-6868-657X
AD  - Institute for Immunity, Transplantation, and Infection, Stanford University 
      School of Medicine, Stanford, CA 94305, USA.
AD  - Department of Microbiology and Immunology, Stanford University School of 
      Medicine, Stanford, CA 94305, USA.
AD  - Howard Hughes Medical Institute, Stanford University School of Medicine, 
      Stanford, CA 94305, USA.
FAU - Bacchetta, Rosa
AU  - Bacchetta R
AUID- ORCID: 0000-0002-0606-6268
AD  - Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative 
      Medicine, Department of Pediatrics, Stanford University School of Medicine, 
      Stanford, CA 94305, USA.
AD  - Center for Definitive and Curative Medicine, Stanford University School of 
      Medicine, Stanford, CA 94305, USA.
FAU - Roncarolo, Maria Grazia
AU  - Roncarolo MG
AUID- ORCID: 0000-0003-1636-1495
AD  - Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative 
      Medicine, Department of Pediatrics, Stanford University School of Medicine, 
      Stanford, CA 94305, USA.
AD  - Center for Definitive and Curative Medicine, Stanford University School of 
      Medicine, Stanford, CA 94305, USA.
AD  - Institute for Stem Cell Biology and Regenerative Medicine, Stanford University 
      School of Medicine, Stanford, CA 94305, USA.
LA  - eng
GR  - P01 CA049605/CA/NCI NIH HHS/United States
GR  - P30 DK116074/DK/NIDDK NIH HHS/United States
GR  - S10 OD018220/OD/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20211027
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
RN  - 0 (CTLA-4 Antigen)
RN  - 0 (Isoantigens)
RN  - 0 (Programmed Cell Death 1 Receptor)
SB  - IM
MH  - CD4-Positive T-Lymphocytes
MH  - CTLA-4 Antigen
MH  - Humans
MH  - *Isoantigens
MH  - *Programmed Cell Death 1 Receptor
MH  - T-Lymphocytes, Regulatory
PMC - PMC9451143
MID - NIHMS1780720
EDAT- 2021/10/28 06:00
MHDA- 2021/11/03 06:00
PMCR- 2022/09/07
CRDT- 2021/10/27 17:14
PHST- 2021/10/27 17:14 [entrez]
PHST- 2021/10/28 06:00 [pubmed]
PHST- 2021/11/03 06:00 [medline]
PHST- 2022/09/07 00:00 [pmc-release]
AID - 10.1126/scitranslmed.abf5264 [doi]
PST - ppublish
SO  - Sci Transl Med. 2021 Oct 27;13(617):eabf5264. doi: 10.1126/scitranslmed.abf5264. 
      Epub 2021 Oct 27.