Quick Links

Defective CD8 Signaling Pathways Delay Rejection in Older Recipients.

Authors: Damanpreet S Bedi|||Felix Krenzien|||Markus Quante|||Hirofumi Uehara|||Karoline Edtinger|||Guangxiang Liu|||Christian Denecke|||Anke Jurisch|||Irene Kim|||Hongmei Li|||Xiaodong Yuan|||Xupeng Ge|||Abdallah ElKhal|||Stefan G Tullius

Journal: Transplantation

Publication Type: Journal Article

Date: 2016

DOI: 10.1097/TP.0000000000000886

ID: 26356176

Affiliations:

Affiliations

    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.|||||||||||||||||||||||||||||||||||||||

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.


Chemical List

    Ccl3 protein, mouse|||Chemokine CCL3|||Homeodomain Proteins|||Il2rb protein, mouse|||Interleukin-2 Receptor beta Subunit|||RAG-1 protein|||CD40 Ligand|||Interferon-gamma