Critical roles of lysosomal acid lipase in T cell development and function.
Lysosomal acid lipase (LAL) cleaves cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in lysosomes. In LAL gene-knockout (lal(-/-)) mice, blockage of cholesteryl ester and triglyceride metabolism led to abnormal organization of the thymus and spleen, as well as neutral lipid accumulation in these organs. LAL deficiency impaired T cell development in the thymus. Peripheral T cells were reduced dramatically in lal(-/-) mice, due largely to increased apoptosis and decreased proliferation of lal(-/-) T cells in the thymus and peripheral compartments. These lal(-/-) T cells lost the ability to respond to T cell receptor stimulation, including reduced expression of cell surface receptor CD69, abolishment of T cell proliferation, and decreased expression of T lymphokines after stimulation by either anti-CD3 plus anti-CD28 or phorbol-12-myristate-13-acetate and ionomycin. Differentiation of Th1 and Th2 CD4(+) effector lymphocytes by T cell receptor stimulation was blocked in lal(-/-) mice. The ratio of CD4(+)CD25(+)FoxP3(+) Tregs to CD4(+) T cells was increased in lal(-/-) spleens. Bone marrow chimeras demonstrated retardation of T cell development and maturation in lal(-/-) mice due to defects in T cell precursors. Therefore, LAL, its downstream genes, and lipid mediators all play essential roles in development, homeostasis, and function of T cells. The altered development and function of lal(-/-) T cells contributes to disease formation in various organs during LAL deficiency.
Qu
Peng
P
The Center for Immunobiology, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 635 Barnhill Dr., Indianapolis, IN 46202, USA.
Du
Hong
H
Wilkes
David S
DS
Yan
Cong
C
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D008078:Cholesterol, LDL / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002787:Sterol Esterase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology*; D013950:Thymus Gland / Q000201:enzymology / Q000276:immunology / Q000473:pathology
D017304:Annexin A5; D008078:Cholesterol, LDL; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D002787:Sterol Esterase