期刊
BLOOD
卷 117, 期 20, 页码 5532-5540出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-11-318675
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资金
- National Institutes of Health (NIH) [RO1HL49915, R01 AI39480]
- Department of Defense, Air Force Office of Scientific Research, National Defense Science and Engineering Graduate (NDSEG) [32 CFR 168a]
- National Cancer Institute (NCI) Comprehensive Cancer Center [CA21765]
- American Lebanese Syrian Associated Charities (ALSAC)
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. (Blood.2011; 117(20):5532-5540)
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