TY - JOUR
T1 - In CD4+ T-cell-induced diabetes, macrophages are the final effector cells that mediate islet β-cell killing
T2 - Studies from an acute model
AU - Calderon, Boris
AU - Suri, Anish
AU - Unanue, Emil R.
N1 - Funding Information:
Supported by the National Institutes of Health and the Kilo Diabetes and Vascular Research Foundation.
PY - 2006/12
Y1 - 2006/12
N2 - To understand better how diabetogenic CD4+ T cells induce islet β-cell death and cause diabetes, a transfer model of acute diabetes using the diabetogenic CD4+ BDC2.5 T-cell clone was established. Transfer of activated BDC T cells into NOD.scid mice resulted in diabetes within a week, characterized by strong inflammatory reaction. Electron micrographs of pancreas depicted macrophages in close contact with β cells that exhibited signs of apoptosis. Transfer into irradiated recipients inhibited inflammation and the development of diabetes, demonstrating an obligatory role for leukocytes. Selective depletion of neutrophils or natural killer cells had no effect on diabetes induced by BDC2.5 T cells. In contrast, in vivo depletion of phagocytic cells by injection of liposomes containing clodronate abolished diabetes, although inflammation remained present and was characterized mainly by neutrophil infiltration. Treatment with clodronate-liposomes did not affect the antigen-presenting cells within the pancreas. Last, activated macrophages isolated from infiltrated pancreas exhibited cytolytic activity toward primary islet β cells. Taken together, these results demonstrate that activated macrophages are the key cells mediating islet β-cell death induced by activated CD4+ T cells.
AB - To understand better how diabetogenic CD4+ T cells induce islet β-cell death and cause diabetes, a transfer model of acute diabetes using the diabetogenic CD4+ BDC2.5 T-cell clone was established. Transfer of activated BDC T cells into NOD.scid mice resulted in diabetes within a week, characterized by strong inflammatory reaction. Electron micrographs of pancreas depicted macrophages in close contact with β cells that exhibited signs of apoptosis. Transfer into irradiated recipients inhibited inflammation and the development of diabetes, demonstrating an obligatory role for leukocytes. Selective depletion of neutrophils or natural killer cells had no effect on diabetes induced by BDC2.5 T cells. In contrast, in vivo depletion of phagocytic cells by injection of liposomes containing clodronate abolished diabetes, although inflammation remained present and was characterized mainly by neutrophil infiltration. Treatment with clodronate-liposomes did not affect the antigen-presenting cells within the pancreas. Last, activated macrophages isolated from infiltrated pancreas exhibited cytolytic activity toward primary islet β cells. Taken together, these results demonstrate that activated macrophages are the key cells mediating islet β-cell death induced by activated CD4+ T cells.
UR - http://www.scopus.com/inward/record.url?scp=34548359992&partnerID=8YFLogxK
U2 - 10.2353/ajpath.2006.060539
DO - 10.2353/ajpath.2006.060539
M3 - Article
C2 - 17148676
AN - SCOPUS:34548359992
SN - 0002-9440
VL - 169
SP - 2137
EP - 2147
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -