title: Rapamycin-treated human endothelial cells preferentially activate allogeneic regulatory T cells.
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.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8089, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.forename: Tai
authors.initials: T
authors.lastname: Yi
authors.forename: Lingfeng
authors.initials: L
authors.lastname: Qin
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Maldonado
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: von Andrian
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kulkarni
authors.forename: George
authors.initials: G
authors.lastname: Tellides
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Pober
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001158:Arteries / Q000637:transplantation; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007165:Immunosuppression Therapy; D015850:Interleukin-6 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D016513:Mice, SCID; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D000076223:Regulatory-Associated Protein of mTOR; D020123:Sirolimus / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014184:Transplantation, Homologous
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D034741:RNA, Small Interfering; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus