MHC CLASS II-DEPENDENT ABNORMAL REACTIVITY TOWARD BACTERIAL SUPERANTIGENS IN IMMUNE CELLS OF NOD MICE

Superantigens have been implicated in the pathogenesis of type I diabe tes and other immune-mediated diseases. We therefore tested the hypoth esis of an abnormal reactivity of the immune system toward bacterial s uperantigens during the prediabetic phase. For this purpose, splenocyt es from NOD (H-2(g7)) mice were exposed to two well-characterized supe rantigens: Staphylococcal aureus enterotoxin-B (SEB) and toxic shock s yndrome toxin-1 (TSST-1). Cells from BALB/c (H-2(d)) and C57BL/6 (H-2( b)) mice as well as those from NON (H-2(non)) and NOR (H-2(g7)) mice w ere used as controls. After 72 h of co-culture with the superantigens or the mitogen concanavalin A (Con A), proliferative response and mito chondrial activity were determined. In the culture supernatants, the c ytokines gamma-interferon (IFN-gamma) and interleukin 10 (IL-10) were measured. Striking similarities between NOD cells and major histocompa tiblity complex (MHC)-identical NOR cells could be observed with regar d to a low proliferative and mitochondrial response to SEB, accompanie d by a normal response to TSST-1 and Con A, respectively. In addition, only NOD and NOR spleen cells were low producers of the T-helper 1 (T h1) cytokine IFN-gamma in response to SEB. Conversely, abnormally high IFN-gamma levels were induced by TSST-1 in NOD and NOR spleen cells. The cytokine response to Con A was also biased toward IFN-gamma in bot h NOD and NOR. Since IFN-gamma and IL-10 are crucial disease-promoting or -protecting mediators in prediabetic NOD mice, superantigens may a ffect pathogenesis by acting on the Th1/Th2 cytokine balance. The low responder status toward SEB in NOD spleen cells may be of pathogenetic relevance in view of recent findings that the insulin B-chain also in teracts with the SEB binding site on MHC class II molecules. In conclu sion, we show here that immune cells from mice with a diabetes-associa ted MHC type respond differently to common environmental superantigens than do immune cells from control strains.