title: Defective CD8 Signaling Pathways Delay Rejection in Older Recipients.
abstract: CD8+ T cells play a cardinal feature in response to alloantigens and are able to generate effector/memory T cells independently from CD4+ T cells. To investigate the impact of aging on CD8 T cells, we used a fully mismatched mouse skin transplant model. Our findings showed a prolonged allograft survival in older recipients associated with a significant increase of CD4+ and CD8+ CD44high CD62Llow effector/memory T cells and a reduced systemic IFNγ production. When reconstituting young CBA Rag-1 mice that lack mature T and B cells with old CD8+ T cells expressing clonal anti-H2K T cell receptor (TCR) alloreactive for MHC I, graft survival was significantly prolonged and comparable to those receiving young CD8+ T cells. Moreover, our data showed that reduced systemic IFNγ levels observed in old recipients had been linked to a compromised expression of the IL-2R β subunit (CD122) by old CD8+ T cells. In addition, we observed an impaired IFNγ production on IL-2 receptor activation. At the same time, gene profiling analysis of old CD8 T cells demonstrated reduced chemokine ligand-3 and CD40L expression that resulted in compromised CD8+ T cell/dendritic cell communication, leading to impaired migratory and phagocytic activity of CD11c cells.Collectively, our study demonstrated that aging delays allograft rejection. CD8 T cells play a critical role in this process linked to a compromised production of IFNγ, in addition to a defective IL-2 receptor signaling machinery and a defective communication between CD8 T cells and dendritic cells.
authors.affiliation: 1 Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. 2 Department of Multi-Organ Transplantation, William Beaumont Hospital, Oakland University William Beaumont School of Medicine, Royal Oak, MI. 3 Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.
authors.forename: Damanpreet S
authors.initials: DS
authors.lastname: Bedi
authors.forename: Felix
authors.initials: F
authors.lastname: Krenzien
authors.forename: Markus
authors.initials: M
authors.lastname: Quante
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Uehara
authors.forename: Karoline
authors.initials: K
authors.lastname: Edtinger
authors.forename: Guangxiang
authors.initials: G
authors.lastname: Liu
authors.forename: Christian
authors.initials: C
authors.lastname: Denecke
authors.forename: Anke
authors.initials: A
authors.lastname: Jurisch
authors.forename: Irene
authors.initials: I
authors.lastname: Kim
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Yuan
authors.forename: Xupeng
authors.initials: X
authors.lastname: Ge
authors.forename: Abdallah
authors.initials: A
authors.lastname: ElKhal
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Tullius
mesh_terms: D019264:Adoptive Transfer; D000367:Age Factors; D000375:Aging / Q000235:genetics / Q000276:immunology*; D064591:Allografts; D000818:Animals; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication; D002465:Cell Movement; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D019672:Genes, T-Cell Receptor; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D006085:Graft Survival; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D053646:Interleukin-2 Receptor beta Subunit / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010587:Phagocytosis; D015398:Signal Transduction; D016038:Skin Transplantation / Q000009:adverse effects*; D013997:Time Factors
chemical_list: C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D018398:Homeodomain Proteins; C508022:Il2rb protein, mouse; D053646:Interleukin-2 Receptor beta Subunit; C064658:RAG-1 protein; D023201:CD40 Ligand; D007371:Interferon-gamma