Epigenetic landscape, key transcriptional regulators, and in vivo identification of human Tr1 cells
(1) Cepika AM (2) Amaya L (3) Waichler C (4) Narula M (5) Mantilla M (6) Thomas BC (7) Chen PP (8) Freeborn RA (9) Pavel-Dinu M (10) Nideffer J (11) Porteus M (12) Bacchetta R (13) Mller F (14) Greenleaf WJ (15) Chang HY (16) Roncarolo MG
Investigating type 1 regulatory CD4+ T (Tr1) cells induced from conventional Foxp3-CD4+ T cells exposed to antigen-presenting tolerogenic DCs and IL-10, Cepika et al. used multiomic profiling and functional genomics to identify IRF4, BATF, and MAF as key transcription factors involved in human Tr1 cell differentiation, phenotype, and function. While Tr1 cells shared some features with Tregs, they showed distinct clonal expansion and functionality. A transcriptional signature for Tr1 cells was defined and successfully identified Tr1 cells in data from Tr1 therapy (T-allo10)-treated patient peripheral blood, high-TMB solid human tumors, and mice treated with a high-dose neoantigen vaccine.
Contributed by Lauren Hitchings
(1) Cepika AM (2) Amaya L (3) Waichler C (4) Narula M (5) Mantilla M (6) Thomas BC (7) Chen PP (8) Freeborn RA (9) Pavel-Dinu M (10) Nideffer J (11) Porteus M (12) Bacchetta R (13) Mller F (14) Greenleaf WJ (15) Chang HY (16) Roncarolo MG
Investigating type 1 regulatory CD4+ T (Tr1) cells induced from conventional Foxp3-CD4+ T cells exposed to antigen-presenting tolerogenic DCs and IL-10, Cepika et al. used multiomic profiling and functional genomics to identify IRF4, BATF, and MAF as key transcription factors involved in human Tr1 cell differentiation, phenotype, and function. While Tr1 cells shared some features with Tregs, they showed distinct clonal expansion and functionality. A transcriptional signature for Tr1 cells was defined and successfully identified Tr1 cells in data from Tr1 therapy (T-allo10)-treated patient peripheral blood, high-TMB solid human tumors, and mice treated with a high-dose neoantigen vaccine.
Contributed by Lauren Hitchings
ABSTRACT: Type 1 regulatory T (Tr1) cells are CD4(+) T cells with suppressive function that are induced from conventional T cells exposed to persistent or strong antigens. Human Tr1 cells are understudied; the regulators of their antigen-driven differentiation are unknown, and identifying them in tissues, where antigen interactions occur, is challenging. Here, we conducted a multiomic profiling of human antigen-induced Tr1 cells. Using CRISPR-based functional genomics, we uncovered essential roles of transcription factors IRF4, BATF, and MAF in human Tr1 differentiation, phenotype, and function. We also derived a Tr1 transcriptional signature that detects cells with a Tr1 phenotype in single-cell datasets from patients treated with Tr1 therapy and those with solid tumors. Cross-species analysis confirmed this signature identifies bona fide Tr1 cells induced in vivo in a murine solid tumor model. These findings provide a framework for development of Tr1-based and Tr1-targeting therapies and studies of Tr1 cell biology.
Author Info:
(1) Division of General Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA. Division of Hematology, Oncology, Stem Cell Transplantation and R
egenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (2) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA. (3) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (4) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (5) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (6) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (7) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (8) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (9) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Division of Immunology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA. (10) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA, USA. (11) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (12) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (13) Integrative Cellular Biology and Bioinformatics, Saarland University, Saarbrcken, Germany. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. (14) Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. (15) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. Center for Personal Dynamic Regulome, Stanford University School of Medicine, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA. (16) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
