Development of the T cell receptor repertoire in lpr mice

The development of double-negative (DN; CD4-, CD8-) T cells and their relationship with other T cell subsets in lpr mice remain poorly understood. Based on studies identifying lpr as a mutation in the fas gene, it has been hypothesized that defective apoptosis in the thymus abnormally affects T cell development and results in the lpr phenotype. A review of studies of T cell receptor repertoires in lpr mice, however, suggests that thymic events are mostly normal in lpr mice. Thus, a global defect in negative selection is not apparent in any T cell population, and positive selection of CD4+ and CD8+ subsets appears to be normal. Surprisingly, repertoire studies also suggest that the majority of DN T cells are positively selected on class I, but not class II, MHC molecules. Furthermore, the expansion of the DN T cell population appears to be driven by abnormal peripheral events. Together, these results provide new insights into the role of fas in T cell development and the aberrant T cell lymphoproliferation in lpr mice.