Back to Search
Start Over
Rapamycin-treated human endothelial cells preferentially activate allogeneic regulatory T cells
- Source :
- Journal of Clinical Investigation. 123:1677-1693
- Publication Year :
- 2013
- Publisher :
- American Society for Clinical Investigation, 2013.
-
Abstract
- Human graft endothelial cells (ECs) can act as antigen-presenting cells to initiate allograft rejection by host memory T cells. Rapamycin, an mTOR inhibitor used clinically to suppress T cell responses, also acts on DCs, rendering them tolerogenic. Here, we report the effects of rapamycin on EC alloimmunogenicity. Compared with mock-treated cells, rapamycin-pretreated human ECs (rapa-ECs) stimulated less proliferation and cytokine secretion from allogeneic CD4+ memory cells, an effect mimicked by shRNA knockdown of mTOR or raptor in ECs. The effects of rapamycin persisted for several days and were linked to upregulation of the inhibitory molecules PD-L1 and PD-L2 on rapa-ECs. Additionally, rapa-ECs produced lower levels of the inflammatory cytokine IL-6. CD4+ memory cells activated by allogeneic rapa-ECs became hyporesponsive to restimulation in an alloantigen-specific manner and contained higher percentages of suppressive CD4+CD25(hi)CD127(lo)FoxP3+ cells that did not produce effector cytokines. In a human-mouse chimeric model of allograft rejection, rapamycin pretreatment of human arterial allografts increased graft EC expression of PD-L1 and PD-L2 and reduced subsequent infiltration of allogeneic effector T cells into the artery intima and intimal expansion. Preoperative conditioning of allograft ECs with rapamycin could potentially reduce immune-mediated rejection.
- Subjects :
- CD4-Positive T-Lymphocytes
Transcriptional Activation
medicine.medical_treatment
T cell
Gene Expression
Mice, SCID
Biology
Lymphocyte Activation
T-Lymphocytes, Regulatory
B7-H1 Antigen
Mice
Human Umbilical Vein Endothelial Cells
medicine
Animals
Humans
Transplantation, Homologous
IL-2 receptor
RNA, Small Interfering
Interleukin-7 receptor
Cells, Cultured
PI3K/AKT/mTOR pathway
Adaptor Proteins, Signal Transducing
Cell Proliferation
Immunosuppression Therapy
Sirolimus
Interleukin-6
TOR Serine-Threonine Kinases
FOXP3
Arteries
Regulatory-Associated Protein of mTOR
General Medicine
Programmed Cell Death 1 Ligand 2 Protein
Molecular biology
Coculture Techniques
Cytokine
medicine.anatomical_structure
Gene Knockdown Techniques
Cancer research
Female
Cytokine secretion
Research Article
medicine.drug
Subjects
Details
- ISSN :
- 00219738
- Volume :
- 123
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....68e868068100ad3c1ca922e6a175c480