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-β signaling into T cells to achieve peripheral CD8 but not CD4 T-cell tolerance in this in vivo system.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adoptive Transfer
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Animals
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Antigens, CD / genetics
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Antigens, CD / immunology*
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Antigens, Surface / genetics
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Antigens, Surface / immunology*
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Apoptosis Regulatory Proteins / deficiency
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / immunology*
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B7-1 Antigen / genetics
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B7-1 Antigen / immunology
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B7-H1 Antigen
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Bone Marrow Transplantation / immunology
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CD4-Positive T-Lymphocytes / immunology
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CD40 Ligand / antagonists & inhibitors
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CD8-Positive T-Lymphocytes / immunology*
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CTLA-4 Antigen
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Female
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Immune Tolerance*
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Lymphocyte Activation Gene 3 Protein
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Membrane Glycoproteins / deficiency
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Models, Immunological
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Peptides / deficiency
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Peptides / genetics
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Peptides / immunology
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Programmed Cell Death 1 Ligand 2 Protein
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Programmed Cell Death 1 Receptor
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Signal Transduction / immunology
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Transforming Growth Factor beta / immunology*
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Transplantation, Homologous
Substances
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Antigens, CD
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Antigens, Surface
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Apoptosis Regulatory Proteins
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B7-1 Antigen
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B7-H1 Antigen
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CTLA-4 Antigen
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Cd274 protein, mouse
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Ctla4 protein, mouse
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Membrane Glycoproteins
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Pdcd1 protein, mouse
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Pdcd1lg2 protein, mouse
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Peptides
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Programmed Cell Death 1 Ligand 2 Protein
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Programmed Cell Death 1 Receptor
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Transforming Growth Factor beta
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CD40 Ligand
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Lymphocyte Activation Gene 3 Protein
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Lag3 protein, mouse