Pancreatic expression of B7 co-stimulatory molecules in the non-obese diabetic mouse.
Expression of the co-stimulatory molecule B7-1 (CD80) on pancreatic beta cells can overcome peripheral T cell tolerance in transgenic models of autoimmune disease. This study aimed to determine if aberrant B7-1 or B7-2 (CD86) expression on pancreatic beta cells is involved in the pathogenesis of autoimmune diabetes in non-obese diabetic (NOD) mice. Immunohistochemical analysis of NOD pancreas sections revealed no evidence of B7-1 or B7-2 expression on pancreatic beta cells at any stage prior to the onset of either spontaneously arising or cyclophosphamide-accelerated diabetes. Likewise, the NOD-derived NIT-1 beta cell line did not express surface B7 or B7-1 mRNA either constitutively or following exposure to IFN-gamma and TNF-alpha, two cytokines known to be present in the insulitis lesion of NOD mice, or cAMP which can induce B7-1 expression on B cells. Both B7-1 and B7-2 were, however, highly expressed on the majority of islet-infiltrating inflammatory cells in NOD mice between days 7 and 12 after the administration of cyclophosphamide which results in accelerated beta cell destruction. Likewise B7-1 and B7-2 were extensively expressed on islet-infiltrating cells present at the time of diabetes onset in NOD SCID mice with adoptively transferred diabetes. By immunohistochemistry and flow cytometry, it was determined that the phenotype of B7+ cells in the pancreas of NOD mice 9 days after cyclophosphamide included a mixture of macrophages and both CD4+ and CD8+ T cells. B7-2 was also expressed on islet-infiltrating cells in the spontaneously occurring diabetes of female NOD mice, but the levels of B7-1 expression were low in comparison with the accelerated models of diabetes. RIP-IL-2 transgenic mice, which have extensive islet infiltration but no autoimmune beta cell destruction, also had virtually no B7-1 expression and a minority of B7-2-expressing inflammatory cells. Thus, the activation of beta cell-specific T cells in NOD mice does not appear to be a result of aberrant expression of B7 on the beta cells. Expression of B7-1 and B7-2 on islet-infiltrating cells is, however, associated with autoimmune beta cell destruction, suggesting a role for the B7-CD28 interaction in this process.
Stephens
L A
LA
Burnet Clinical Research Unit, Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, Victoria, Australia.
Kay
T W
TW
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism*; D051940:B7-2 Antigen; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D007150:Immunohistochemistry; D007376:Interleukin-2 / Q000235:genetics; D007515:Islets of Langerhans / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010641:Phenotype
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D017931:DNA Primers; D007376:Interleukin-2; D008562:Membrane Glycoproteins