Absolute requirement of macrophages for the development and activation of beta-cell cytotoxic CD8(+) T-cells in T-cell receptor transgenic NOD mice

The development of autoimmune diabetes in NOD) mice results from selective destruction of beta-cells by a T-cell-dependent autoimmune process, However , the mechanisms that control the generation of beta-cell cytotoxic T-cells in vivo are poorly understood. We recently established 8.3-T-cell receptor (TCR)-beta transgenic NOD mice that show a selective acceleration of the r ecruitment of CD8(+) T-cells into the islets of prediabetic animals, result ing in rapid beta-cell destruction and early onset of diabetes. This study was initiated to determine the role of macrophages in the development and a ctivation of diabetogenic CDS' T-cells in 8.3-TCR-beta transgenic NOT) mice . Inactivation of macrophages: in these transgenic mice resulted in the com plete prevention of diabetes. When splenic T-cells from macrophage-depleted 8.3-TCR-beta transgenic NOD mice were transfused into severe combined immu nodeficiency disease (NOD.scid) mice? none of the recipients developed diab etes up to 10 weeks after transfer, while most of the recipients of T-cells from age-matched control 8.3-TCR-beta transgenic NOD mice became diabetic. When intact NOD islets were transplanted under the renal capsule of macrop hage-depleted 8.3-TCR-beta transgenic NOD mice, the majority of the grafted islets remained intact, while most of the islets grafted into age-matched, control 8.3-TCR-beta transgenic NOD mice were destroyed within 3 weeks aft er transplantation, The depletion of macrophages in these mice resulted in a decrease in the Th1 immune response along with an increase in the Th2 imm une response because of significant decreases in the expression of macropha ge-derived cytokines, particularly interleukin-12, and a decrease in beta-c ell-specific T-cell activation, as shown by significant decreases in the ex pression of Fas ligand (FasL), CD40 ligand (CD40L), and perforin, as compar ed with control mice. We conclude that macrophages are absolutely required for the development and activation of beta-cell cytotoxic CD8(+) T-cells in 8.3-TCR-beta transgenic NOD mice.