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


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.
Rajasalu
Tarvo
T
Department of Internal Medicine I, University Hospital of Ulm, Ulm,Germany.
Brosi
Helen
H
Schuster
Cornelia
C
Spyrantis
Andreas
A
Boehm
Bernhard Otto
BO
Chen
Lieping
L
Reimann
Jörg
J
Schirmbeck
Reinhold
R
D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics*; D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D006801:Humans; D007328:Insulin / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000473:pathology*; D007371:Interferon-gamma / Q000172:deficiency; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000172:deficiency / Q000235:genetics*; D011498:Protein Precursors / Q000235:genetics
D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D007328:Insulin; D008562:Membrane Glycoproteins; D010455:Peptides; D011498:Protein Precursors; C013737:preproinsulin; D007371:Interferon-gamma