B7-H4 induces donor-specific tolerance in mouse islet allografts

Cell Transplant. 2012;21(1):99-111. doi: 10.3727/096368911X582750. Epub 2011 Sep 16.


Negative cosignaling molecules play an important role in regulating T-cell responses to alloantigen stimulation. We recently reported that adenoviral-mediated transduction of islet allografts with B7-H4 inhibits allograft rejection. In this study, we investigate the mechanism for B7-H4-induced prolongation of mouse islet allograft survival. Streptozotocin-induced diabetic C57BL/6 mice were rendered normoglycemic by renal subcapsular implants of B7-H4-transduced BALB/c islets. Grafts and spleens were removed after days 2, 10, and 60 (n = 8 each) for characterization of kinetics of Foxp3 and interleukin 10 (IL-10) expression. Mixed lymphocyte reaction (MLR) was done at day 60. Ten mice were subjected to nephrectomy at 60 days and then five were implanted with secondary BALB/c islets and five were given third-party CBA/J islets. An increase in Foxp3 and IL-10 mRNA expression was detected in recipients' spleens at day 60 and this was associated with increased quantities of Foxp3(+) cells. Splenocytes at day 60 showed hyporesponsiveness during MLR to alloantigen stimulation. Proliferation was partially restored after CD25(+) T-cell depletion. Secondary BALB/c islets survived for 79 ± 29 days compared with 21 ± 3.6 days for CBA/J islets (p < 0.001). Local expression of B7-H4 induces long-term unresponsiveness to donor-specific alloantigens, and is associated with T regulatory cells, suggesting the development of tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental / surgery*
  • Forkhead Transcription Factors / biosynthesis
  • Graft Survival*
  • Interleukin-10 / biosynthesis
  • Islets of Langerhans / cytology
  • Islets of Langerhans / immunology
  • Islets of Langerhans Transplantation / immunology*
  • Lymphocyte Culture Test, Mixed
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Nephrectomy
  • T-Lymphocytes, Regulatory / immunology
  • Transduction, Genetic
  • Transplantation Tolerance*
  • Transplantation, Homologous
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1 / genetics*
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1 / immunology


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1
  • Vtcn1 protein, mouse
  • Interleukin-10