Deficiency in B7-H1 (PD-L1)/PD-1 Coinhibition Triggers Pancreatic β-Cell Destruction by Insulin-Specific, Murine CD8 T-Cells

Rajasalu, Tarvo
Brosi, Helen
Schuster, Cornelia
Spyrantis, Andreas
Boehm, Bernhard Otto
Chen, Lieping
Reimann, Jörg
Schirmbeck, Reinhold

¹Department of Internal Medicine I, University Hospital of Ulm, Ulm, Germany;
²Department of Internal Medicine and Immunology, University of Tartu, Tartu, Estonia;
³Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Corresponding author: Reinhold Schirmbeck, [email protected].

T.R. and H.B. contributed equally to this study.

Received August 14, 2009

Accepted May 4, 2010

Diabetes 59(8):p 1966-1973, August 2010. | DOI: 10.2337/db09-1135

OBJECTIVE

RIP-B7.1 mice expressing the costimulator molecule B7.1 (CD80) on pancreatic β-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 β-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 β-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 β-cells can trigger pancreatic β-cell-destruction by preproinsulin-specific CD8 T-cells. Hence, regulation of the susceptibility of the β-cells for a preproinsulin-specific CD8 T-cell attack can allow or suppress EAD.