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

Blood. 2011 May 19;117(20):5532-40. doi: 10.1182/blood-2010-11-318675. Epub 2011 Mar 21.


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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / immunology*
  • Antigens, Surface / genetics
  • Antigens, Surface / immunology*
  • Apoptosis Regulatory Proteins / deficiency
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / immunology*
  • B7-1 Antigen / genetics
  • B7-1 Antigen / 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*
  • Lymphocyte Activation Gene 3 Protein
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Immunological
  • Peptides / deficiency
  • Peptides / genetics
  • Peptides / immunology
  • Programmed Cell Death 1 Ligand 2 Protein
  • Programmed Cell Death 1 Receptor
  • Signal Transduction / immunology
  • Transforming Growth Factor beta / immunology*
  • Transplantation, Homologous


  • Antigens, CD
  • Antigens, Surface
  • Apoptosis Regulatory Proteins
  • B7-1 Antigen
  • B7-H1 Antigen
  • CTLA-4 Antigen
  • Cd274 protein, mouse
  • Ctla4 protein, mouse
  • Membrane Glycoproteins
  • Pdcd1 protein, mouse
  • Pdcd1lg2 protein, mouse
  • Peptides
  • Programmed Cell Death 1 Ligand 2 Protein
  • Programmed Cell Death 1 Receptor
  • Transforming Growth Factor beta
  • CD40 Ligand
  • Lymphocyte Activation Gene 3 Protein
  • Lag3 protein, mouse