Opposing roles for Fas ligand and IL-10 in regulating insulitis initiation (101.32)

• Published in: The Journal of immunology (1950) 2011-04, Vol.186 (1_Supplement), p.101-101.32
• Main Authors: Hamad, Abdel Rahim, Uddin, Sophia, Marshall, Andrew, Nakata, Chiaki
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.186.Supp.101.32

Type 1 diabetes (TID), leading autoimmune disease of childhood, is caused by destruction of beta-cells by autoreactive T cells. Despite daily insulin injections, patients often develop cardiovascular complications and there is a need for identifying therapeutic targets to prevent the disease without impinging on host defense. Fas ligand (FasL) can be such a potential target. Fas/FasL interactions primarily regulate T cell homeostasis but not activation. Nevertheless, mutation of FasL (gld) prevents autoimmune diabetes in NOD mice, the widely used model for T1D. Although homozygous gld mutations cause age-dependent lymphoproliferation, limiting the gld mutation to one allele (NOD-gld/+) or treating NOD-wt mice with FasL-neutralizing mAb inhibits insulitis and prevents disease development without causing lymphoproliferation or immunosuppression. Here we show that the gld mutation did not inhibit proliferation and expansion of diabetogenic T cells in pancreatic lymph nodes but inhibited their accumulation in the pancreata. A significant proportion of B cells found in pancreata of NOD-gld/+ mice surface-expressed CD5 and produced IL-10. Neutralization of IL-10 allowed CD4+ T cell accumulation in the pancreas and development of insulitis in NOD-gld/+ mice. The results provide novel mechanistic insights into the disease pathogenesis with potential implications for developing novel T1D therapy.