Defective CD8 Signaling Pathways Delay Rejection in Older Recipients

Transplantation. 2016 Jan;100(1):69-79. doi: 10.1097/TP.0000000000000886.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Age Factors
  • Aging / genetics
  • Aging / immunology*
  • Allografts
  • Animals
  • CD40 Ligand / immunology
  • CD40 Ligand / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Communication
  • Cell Movement
  • Cells, Cultured
  • Chemokine CCL3 / immunology
  • Chemokine CCL3 / metabolism
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Genes, T-Cell Receptor
  • Graft Rejection / genetics
  • Graft Rejection / immunology*
  • Graft Rejection / metabolism
  • Graft Rejection / prevention & control
  • Graft Survival*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Interleukin-2 Receptor beta Subunit / immunology
  • Interleukin-2 Receptor beta Subunit / metabolism
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Inbred DBA
  • Mice, Knockout
  • Phagocytosis
  • Signal Transduction*
  • Skin Transplantation / adverse effects*
  • Time Factors

Substances

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