LAG-3, TGF-beta, and cell-intrinsic PD-1 inhibitory pathways contribute to CD8 but not CD4 T-cell tolerance induced by allogeneic BMT with anti-CD40L

Lucas, C. L., Workman, C. J., Beyaz, S., LoCascio, S., Zhao, G., Vignali, D. A., Sykes, M. (May 2011) LAG-3, TGF-beta, and cell-intrinsic PD-1 inhibitory pathways contribute to CD8 but not CD4 T-cell tolerance induced by allogeneic BMT with anti-CD40L. Blood, 117 (20). pp. 5532-40. ISSN 1528-0020 (Electronic)0006-4971 (Linking)

URL: https://www.ncbi.nlm.nih.gov/pubmed/21422469
DOI: 10.1182/blood-2010-11-318675

Abstract

Administration of a single dose of anti-CD40L mAb at the time of allogeneic BM transplantation tolerizes peripheral alloreactive T cells and permits establishment of mixed hematopoietic chimerism in mice. Once engrafted, mixed chimeras are systemically tolerant to donor Ags through a central deletion mechanism and will accept any donor organ indefinitely. We previously found that the PD-1/PD-L1 pathway is required for CD8 T-cell tolerance in this model. However, the cell population that must express PD-1 and the role of other inhibitory molecules were unknown. Here, we report that LAG-3 is required for long-term peripheral CD8 but not CD4 T-cell tolerance and that this requirement is CD8 cell-extrinsic. In contrast, adoptive transfer studies revealed a CD8 T cell-intrinsic requirement for CTLA4/B7.1/B7.2 and for PD-1 for CD8 T-cell tolerance induction. We also observed that both PD-L1 and PD-L2 are independently required on donor cells to achieve T-cell tolerance. Finally, we uncovered a requirement for TGF-beta signaling into T cells to achieve peripheral CD8 but not CD4 T-cell tolerance in this in vivo system.

Item Type: Paper
Uncontrolled Keywords: Adoptive Transfer Animals Antigens, CD/genetics/*immunology Antigens, Surface/genetics/*immunology Apoptosis Regulatory Proteins/deficiency/genetics/*immunology B7-1 Antigen/genetics/immunology B7-H1 Antigen Bone Marrow Transplantation/immunology CD4-Positive T-Lymphocytes/immunology CD40 Ligand/antagonists & inhibitors CD8-Positive T-Lymphocytes/*immunology CTLA-4 Antigen Female *Immune Tolerance Membrane Glycoproteins/deficiency/genetics/immunology Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Models, Immunological Peptides/deficiency/genetics/immunology Programmed Cell Death 1 Ligand 2 Protein Programmed Cell Death 1 Receptor Signal Transduction/immunology Transforming Growth Factor beta/*immunology Transplantation, Homologous
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells

therapies > bone marrow transplantation
organs, tissues, organelles, cell types and functions > tissues types and functions > signal transduction
CSHL Authors:
Communities: CSHL labs > Beyaz lab
Depositing User: Matt Covey
Date: 19 May 2011
Date Deposited: 02 Feb 2018 19:44
Last Modified: 02 Feb 2018 19:44
PMCID: PMC3109721
Related URLs:
URI: http://repository.cshl.edu/id/eprint/36054

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