Roles for cathepsins S, L, and B in insulitis and diabetes in the NOD mouse.
We developed a panel of non-obese diabetic (NOD) mice deficient in major lysosomal cysteine proteases (cathepsins S, L and B) to identify protease enzymes essential for autoimmune diabetes. Null alleles for cathepsins (Cts) S, L or B were introgressed onto the NOD genetic background with 19 Idd markers at homozygosity. Diabetes onset was determined among females aged up to 6 months. We evaluated insulitis and sialadenitis in tissues using histology and computer assisted morphology. NOD mice deficient in Ctss or Ctsb were partially protected from diabetes with incidence at 33% and 28%, respectively, versus wild-type NOD (69%; p < 0.00001). NODs lacking cathepsin L (Ctsl-/-) are completely protected from IDDM, as originally shown by others. Ctsl, Ctss, or Ctsb heterozygous mice were able to develop IDDM, although incidence levels were significantly lower for Ctsb+/- (50%) and Ctsl+/- (55%) as compared to NODs (69%; p < 0.03). Ctsl-/- mice contain functional, diabetogenic T cells and an enriched Foxp3+ regulatory T cell population, and diabetes resistance was due to the presence of an expanded population of regulatory T cells. These data provide additional information about the potency of the diabetogenic T cell population in Ctsl-/- mice which were comparable in potency to wild-type NOD mice. These data illustrate the critical contribution of each of these proteases in determining IDDM in the NOD mouse and provide a useful set of models for further studies.
Hsing
Lianne C
LC
Department of Immunology and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98109-8050, USA.
Kirk
Elizabeth A
EA
McMillen
Timothy S
TS
Hsiao
Shuo-Hung
SH
Caldwell
Mark
M
Houston
Barbara
B
Rudensky
Alexander Y
AY
LeBoeuf
Renee C
RC
D017668:Age of Onset; D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis; D002401:Cathepsin B / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D056668:Cathepsin L / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002403:Cathepsins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D008231:Lymphopenia; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010195:Pancreatitis; D012793:Sialadenitis; D016176:T-Lymphocyte Subsets / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000473:pathology
D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D002403:Cathepsins; D002401:Cathepsin B; D056668:Cathepsin L; C028217:cathepsin S