The CD4 T cell-deficient mouse mutation nackt (nkt) involves a deletion in the cathepsin L (Ctsl) gene

We recently reported a novel autosomal recessive mouse mutation designated nackt (nkt). Homozygous mutant mice have diffuse alopecia and a marked reduction in the proportion of CD4(+) T cells in the thymus and peripheral lymphoid tissues. Here we show that the CD4 T-cell deficiency is due to a defect in the thymic microenvironment rather than the hematopoietic compartment. Furthermore, we identified the molecular basis of the mutant phenotype by demonstrating that the nkt mutation represents a 118-bp deletion of the cathepsin L (Ctsl) gene which is required for degradation of the invariant chain, a critical chaperone for major histocompatibility complex class II molecules. This finding explains the similarities in skin and immune defects observed in nkt/nkt and Ctsl -/- mice. The data reported here provide further in vivo evidence that the lysosomal cysteine protease cathepsin L plays a critical role in CD4(+) T-cell selection in the thymus.