Deficiency in B7-H1 (PD-L1)/PD-1 coinhibition triggers pancreatic beta-cell destruction by insulin-specific, murine CD8 T-cells

Diabetes. 2010 Aug;59(8):1966-73. doi: 10.2337/db09-1135. Epub 2010 May 18.

Abstract

Objective: RIP-B7.1 mice expressing the costimulator molecule B7.1 (CD80) on pancreatic beta-cells are a well established model to characterize preproinsulin-specific CD8 T-cell responses and experimental autoimmune diabetes (EAD). Different immunization strategies could prime preproinsulin-specific CD8 T-cells in wild-type C57BL/6 (B6) mice, but did not induce diabetes. We tested whether altering the B7-H1 (PD-L1) coinhibition on pancreatic beta-cells can reveal a diabetogenic potential of preproinsulin-specific CD8 T-cells.

Research design and methods: DNA-based immunization and adoptive T-cell transfers were used to characterize the induction of preproinsulin-specific CD8 T-cell responses and EAD in RIP-B7.1, B6, B7-H1(-/-), PD-1(-/-) or bone marrow chimeric mice.

Results: Preproinsulin-specific CD8 T-cells primed in B6 mice revealed their diabetogenic potential after adoptive transfer into congenic RIP-B7.1 hosts. Furthermore, preproinsulin-specific CD8 T-cells primed in anti-B7-H1 antibody-treated B6 mice, or primed in B7-H1(-/-) or PD-1(-/-) mice induced EAD. Immunization of bone marrow chimeric mice showed that deficiency of either B7-H.1 in pancreatic beta-cells or of PD-1 in autoreactive CD8 T-cells induced EAD.

Conclusions: An imbalance between costimulator (B7.1) and coinhibitor (B7-H1) signals on pancreatic beta-cells can trigger pancreatic beta-cell-destruction by preproinsulin-specific CD8 T-cells. Hence, regulation of the susceptibility of the beta-cells for a preproinsulin-specific CD8 T-cell attack can allow or suppress EAD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-1 Antigen / genetics*
  • B7-H1 Antigen
  • CD8-Positive T-Lymphocytes / immunology*
  • Diabetes Mellitus, Type 1 / immunology*
  • Humans
  • Insulin / genetics
  • Insulin-Secreting Cells / immunology*
  • Insulin-Secreting Cells / pathology*
  • Interferon-gamma / deficiency
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Peptides / deficiency
  • Peptides / genetics*
  • Protein Precursors / genetics

Substances

  • B7-1 Antigen
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Insulin
  • Membrane Glycoproteins
  • Peptides
  • Protein Precursors
  • preproinsulin
  • Interferon-gamma