The role of Fas in the immune system biology of IL-2R alpha knockout mice: interplay among regulatory T cells, inflammation, hemopoiesis, and apoptosis.
Introducing lpr mutation prevents early mortality associated with IL-2Ralpha knockout (KO) mice, prompting us to determine the role of Fas in the immune system biology of IL-2Ralpha KO mice. Consistent with a defect in CD4+CD25+ regulatory T (Treg) cell expression, spontaneous lymphocyte activation in lymphoid organs was observed in 6-wk-old mice. In 16- to 22-wk-old mice, infiltration of leukocytes was observed in bone marrow, colon, lung, pancreas, lacrimal gland, and salivary gland, but not in heart, thyroid, liver, stomach, small intestine, ovary, and kidney. In the lymphocytes-infiltrated bone marrow, B cell lymphopoiesis was blocked at pro-B to pre-B/immature B stage, culminating in an age-dependent B cell loss in the periphery. These phenotypes were also observed in IL-2Ralpha KO mice bearing the lpr mutation (DM mice), indicating Treg cell function and the phenotypes attributed directly to Treg cell abnormality are largely Fas-independent. However, anemia and body weight loss were partially prevented, tissue cell apoptosis was inhibited, and lifespan was improved in the DM mice, demonstrating Fas-dependent elements in these processes. Our age-dependent, lifelong analysis of IL-2Ralpha KO and DM mice supports a CD4+CD25+ Treg cell-based mechanism for the abnormal immune system biology observed in IL-2Ralpha KO mice and provides a global view of the interplays among Treg cells, multiorgan inflammation, hemopoiesis, and apoptosis.
Sharma
Rahul
R
Division of Rheumatology and Immunology, Department of Internal Medicine, University of Virginia, Charlottesville, VA 22908-0412, USA.
Bagavant
Harini
H
Jarjour
Wael N
WN
Sung
Sun-Sang J
SS
Ju
Shyr-Te
ST
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology*; D017099:IgG Deficiency / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D053645:Interleukin-2 Receptor alpha Subunit; D008136:Longevity / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout / Q000235:genetics / Q000276:immunology*; D018123:Receptors, Interleukin / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D019014:fas Receptor / Q000235:genetics / Q000502:physiology*
C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D018123:Receptors, Interleukin; D019014:fas Receptor