Critical Roles of Lysosomal Acid Lipase in T Cell Development and Function

摘要

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.