Unexpected acceleration of type 1 diabetes by transgenic expression of B7-H1 in NOD mouse peri-islet glia.
OBJECTIVE
Autoimmune target tissues in type 1 diabetes include pancreatic β-cells and peri-islet Schwann cells (pSC)--the latter active participants or passive bystanders in pre-diabetic autoimmune progression. To distinguish between these alternatives, we sought to suppress pSC autoimmunity by transgenic expression of the negative costimulatory molecule B7-H1 in NOD pSC.


METHODS
A B7-H1 transgene was placed under control of the glial fibrillary acidic protein (GFAP) promoter. Transgenic and wild-type NOD mice were compared for transgene PD-1 affinities, diabetes development, insulitis, and pSC survival. Mechanistic studies included adoptive type 1 diabetes transfer, B7-H1 blockade, and T-cell autoreactivity and sublineage distribution.


RESULTS
Transgenic and endogenous B7-H1 bound PD-1 with equal affinities. Unexpectedly, the transgene generated islet-selective CD8(+) bias with accelerated rather than suppressed diabetes progression. T-cells of diabetic transgenics transferred type 1 diabetes faster. There were no earlier pSC losses due to conceivable transgene toxicity, but transgenic pSC loss was enhanced by 8 weeks, preceded by elevated GFAP autoreactivity, with high-affinity T-cells targeting the major NOD K(d)-GFAP epitope, p253-261. FoxP3(+) regulatory T- and CD11c(+) dendritic cell pools were unaffected.


CONCLUSIONS
In contrast with transgenic B7-H1 in NOD mouse β-cells, transgenic B7-H1 in pSC promotes rather than protects from type 1 diabetes. Here, ectopic B7-H1 enhanced the pathogenicity of effector T-cells, demonstrating that pSC can actively impact diabetes progression-likely through modification of intraislet T-cell selection. Although pSC cells emerge as a new candidate for therapeutic targets, caution is warranted with regard to the B7-H1-PD1 axis, where B7-H1 overexpression can lead to accelerated autoimmune disease.
Neuroscience and Mental Health Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
Jason
J
Yantha
Hubert
H
Tsui
Shawn
S
Winer
Aihua
A
Song
Ping
P
Wu
Geoff
G
Paltser
James
J
Ellis
H-Michael
HM
Dosch
D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D018122:B7-1 Antigen / Q000235:genetics; D060890:B7-H1 Antigen; D003713:Dendritic Cells / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000473:pathology; D015870:Gene Expression; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D006651:Histocytochemistry; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology*; D007515:Islets of Langerhans / Q000473:pathology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010455:Peptides / Q000235:genetics; D011401:Promoter Regions, Genetic; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology
D015703:Antigens, CD; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C498919:Cd274 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D008562:Membrane Glycoproteins; D010455:Peptides