Abstract
DNAX accessory protein-1 (DNAM-1, CD226) is a co-stimulatory and adhesion molecule expressed mainly by natural killer cells and T cells. DNAM-1 and its two ligands CD112 and CD155 are important in graft-versus-host disease, but their role in solid organ transplantation is largely unknown. We investigated the relevance of this pathway in a mouse kidney transplantation model. CD112 and CD155 are constitutively expressed on renal tubular cells and strongly upregulated in acutely rejected renal allografts. In vitro DNAM-1 blockade during allogeneic priming reduced the allospecific T cell response but not the allospecific cytotoxicity against renal tubular epithelial cells. Accordingly, absence of DNAM-1 in recipient mice or absence of CD112 or CD155 in the kidney allograft did not significantly influence renal function and severity of rejection after transplantation, but led to a higher incidence of infarcts in CD112 and CD155 deficient kidney allografts. Thus, DNAM-1 blockade is not effective in preventing transplant rejection. Despite of being highly expressed, CD112 and CD155 do not appear to play a major immunogenic role in kidney transplantation. Considering the high incidence of renal infarcts in CD112 and CD155 deficient grafts, blocking these molecules might be detrimental.
Highlights
Antigen recognition via the T cell receptor is not sufficient for a complete T cell activation
Quantitative RT-PCR of whole renal tissue indicated a modest up-regulation of mRNA coding for both CD112 and CD155 in syngeneic grafts compared to naïve kidneys (CD112: 1.52 fold increase, n = 5, p = 0.03; CD155: 1.42 fold increase, n = 5, p = 0.06)
We found that in allogeneic immune responses the DNAM-1 signaling pathway is involved in T cell priming, but not in the effector phase of the immune response
Summary
Antigen recognition via the T cell receptor is not sufficient for a complete T cell activation. A collection of costimulatory and coinhibitory signals modulates the complex interaction between T cells and antigen presenting cells (APCs) in the process of T cell priming and between T cells and target cells in the effector phase of the immune response [1, 2]. Because of the fundamental role of T cell costimulation in the activation of donor reactive T cells after transplantation, costimulation blockade has become a promising target for the development of more specific and less toxic strategies to prevent rejection and induce tolerance [3]. PLOS ONE | DOI:10.1371/journal.pone.0147951 February 3, 2016
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