SELECTION OF THE T-CELL RECEPTOR REPERTOIRE IN LPR MICE

The development of double-negative (CD4-, CD8-) T cells and other T ce ll subsets in lymphoproliferation (lpr) mice continues to be poorly de fined. Recent studies indicate that lpr is a mutation of a receptor me diating apoptosis. It has thus been hypothesized that T cell developme nt in the thymus should be abnormally affected. In this study, we anal yzed the TCR Vbeta repertoire of double-negative T cells as well as CD 4+ and CD8+ single-positive subsets in various lpr and matched non-lpr strains. Particular comparisons were made to determine the influence of different class I and class II molecules on repertoire formation. T he data demonstrate that positive and negative selection of the CD4+ a nd CD8+ subsets are normal in lpr mice when compared with non-lpr cong enic mice. Surprisingly, the results also suggest that double-negative T cells are mostly selected on class I MHC molecules in a pattern sim ilar to the CD8+ population, and that T cells positively selected on c lass II MHC antigens may be absent from the double-negative population . In all lpr strains, we also found an increased percentage of double- negative Vbeta8.3+ cells out of proportion to levels in the CD4+ or CD 8+ subsets. Longitudinal studies and studies in thymectomized animals showed that this increase reflects a peripheral process selectively af fecting Vbeta8.3+ double-negative T cells. Together, these repertoire data provide new insight into the effect of the lpr genetic defect on T cell development and the derivation of double-negative T cells. Desp ite the role of Fas in apoptosis and the abnormal expression of this g ene in lpr mice, the present results support the hypothesis that thymi c events are relatively normal in lpr mice, and that the double-negati ve T cells are mostly class I MHC selected and expanded by abnormal pe ripheral processes.