FAS (CD95)-INDEPENDENT ISLET ALLOGRAFT DESTRUCTION MEDIATED BY CD4+ ISLET-SPECIFIC T CELLS

Abstract

120 Previous studies have shown that pathogenic, islet-specific CD8 T cells derived from non-obese diabetic (NOD) mice are restricted to MHC antigens expressed by islet β cells. However, islet-specific CD4 T cells have also been shown to trigger islet destruction in vivo independently from CD8 T cells or B cells. One example of CD4+, pathogenic T cells is illustrated by BDC2.5 T cell receptor (TCR) transgenic mice specific for an unidentified islet antigen presented in association with NOD MHC class II (I-Ag7). The nature of such CD4-mediated islet damage is unclear, since islets are generally regarded as being devoid of class II MHC antigen expression. Purpose: The purpose of this study was to determine whether BDC2.5 TCR transgenic T cells could mediate the destruction of islet allografts that were MHC class II disparate to the NOD. Methods: NOD BDC2.5 TCR transgenic mice were bred onto the NODscid background to eliminate detectable non-transgenic (endogenous) TCR specificities (BDC2.5scid). BDC2.5scid T cells failed to respond to allogeneic C57Bl/6 (B6, H-2b) antigen presenting cells (APC) in vitro but did respond to either NOD or B6 islet cell antigen in association with NOD APCs. Streptozotocin-induced diabetic NODscid mice were grafted with B6 islet or thyroid grafts at opposite poles of the left kidney capsule. Recipients were either untreated, or were challenged with 106 BDC2.5scid spleen cells intraperitoneally. Results: BDC2.5scid T cells triggered rapid destruction of 7/7 B6 islet allografts in a mean of 11 days post T cell transfer. However, none of the B6 thyroid grafts were damaged, indicating the tissue-specificity of the response. Furthermore, BDC2.5scid also mediated acute destruction of Fas-deficient B6 lpr (5/5 grafts destroyed in 14 days), indicating that interaction with Fas on the target islet was not required for target damage. Conclusions: These results indicate that islet-specific BDC2.5scid T cells can rapidly trigger destruction of islet allografts that cannot express the MHC class II restriction molecule required for CD4 T cell recognition. This result supports an inflammatory mechanism of islet damage resulting from CD4 T cell interaction with host-type APCs in vivo. Furthermore, this effector pathway appears to be Fas-independent, in distinction from previous findings with islet-specific CD8 T cells that have been shown to induced islet damage via a Fas-dependent mechanism.