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)
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: | https://repository.cshl.edu/id/eprint/36054 |
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