The CD4 T cell-deficient mouse mutation nackt (nkt) involves a deletion in the cathepsin L (CtsI) 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.
Benavides
F
F
Department of Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Smithville 78957, USA. fbenavides@sprd1.mdacc.tmc.edu
Venables
A
A
Poetschke Klug
H
H
Glasscock
E
E
Rudensky
A
A
Gómez
M
M
Martin Palenzuela
N
N
Guénet
J L
JL
Richie
E R
ER
Conti
C J
CJ
D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes; D056668:Cathepsin L; D002403:Cathepsins / Q000235:genetics*; D002874:Chromosome Mapping; D003546:Cysteine Endopeptidases; D018076:DNA, Complementary; D010450:Endopeptidases; D017353:Gene Deletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D013950:Thymus Gland
D018076:DNA, Complementary; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D056668:Cathepsin L; C534278:Ctsl protein, mouse