Defective M _ aintenance of T cell Tolerance to a Superantigen in MRI

In normal mice neonatal injection of staphylococcal enterotoxin B (SEB) induces tolerance in T cells that express reactive T cell receptor (TCK) V/~ regions. To determine if a T cell neonatal defect was present in MRL-Ipr/Ipr mice, 20 #g of SEB was injected intraperitoneally every other day into VBS.2 TCR transgenic and nontransgenic MR.b + / + and MKL-Ipr/Ipr mice from birth to 2 wk of age. At 2 wk of age, V~8 + T cells were depleted, and SEB reactivity was lost, in spleen, lymph node, and thymus. These effects were equivalent in + /+ and Ipr/lpr SEB-tolerized mice. However, MILL-Ipr/Ipr mice failed to maintain neonatal tolerance. By 4 wk of age, there was a dramatic increase in T cells expressing V~8.2 in the peripheral lymph nodes of MRblpr/lt,r mice but not MRD + / + mice. In vitro stimulation with SEB or TCR crosslinking revealed a total loss of neonatal tolerance 2 wk after cessation of SEB treatment in Ipr/Ipr mice, but not + /+ mice. The time-course of recovery of V~8 + T cells and reactivity to SEB and TCR crosslinking in the thymus of MRL-Ipr/Ipr mice was similar to that in the lymph node. Thymectomy at 2 wk of age eliminated tolerance loss in lymph nodes of MtLL-Ipr/Ipr mice at 4 wk of age, indicating that loss of peripheral tolerance was due to the emigration of untolerized T cells from the thymus. Challenge of neonatally tolerized MRb.lpr/Ipr mice with SEB (100 #g, i.p.) at 8 wk of age resulted in a dramatic onset of T cell-mediated autoimmune disease characterized by 30% weight loss and 60% morality. This indicated that loss of tolerance to SEB also occurred in vivo. In contrast, neonatally tolerized MRL+ / + mice remained totally unresponsive to SEB challenge and did not undergo any detectable weight loss. These results suggest that there is normal induction of neonatal tolerance to SEB in lpr/Ipr mice, but that tolerance is not maintained after the tolerizing antigen is removed. This loss of neonatal tolerance can lead to severe weight loss and death on exposure to the tolerizing antigen later in life.