Critical roles of lysosomal acid lipase in T cell development and function

Am J Pathol. 2009 Mar;174(3):944-56. doi: 10.2353/ajpath.2009.080562. Epub 2009 Jan 29.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Annexin A5 / metabolism
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / physiology
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cholesterol, LDL / blood
  • Cytokines / metabolism
  • Flow Cytometry
  • Immunohistochemistry
  • Immunosuppression
  • Lymphocyte Activation
  • Mice
  • Mice, Knockout
  • Receptors, Antigen, T-Cell / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spleen / enzymology
  • Spleen / immunology
  • Spleen / pathology
  • Sterol Esterase / deficiency*
  • Sterol Esterase / genetics*
  • Sterol Esterase / metabolism
  • T-Lymphocytes / enzymology*
  • T-Lymphocytes / immunology*
  • Thymus Gland / enzymology
  • Thymus Gland / immunology
  • Thymus Gland / pathology

Substances

  • Annexin A5
  • Cholesterol, LDL
  • Cytokines
  • Receptors, Antigen, T-Cell
  • Sterol Esterase