Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling

J Clin Invest. 2001 Jul;108(1):131-41. doi: 10.1172/JCI10360.

Abstract

Adenosine deaminase (ADA) deficiency in humans results in a severe combined immunodeficiency (SCID). This immunodeficiency is associated with severe disturbances in purine metabolism that are thought to mediate lymphotoxicity. The recent generation of ADA-deficient (ADA(-/-)) mice has enabled the in vivo examination of mechanisms that may underlie the SCID resulting from ADA deficiency. We demonstrate severe depletion of T and B lymphocytes and defects in T and B cell development in ADA(-/-) mice. T cell apoptosis was abundant in thymi of ADA(-/-) mice, but no increase in apoptosis was detected in the spleen and lymph nodes of these animals, suggesting that the defect is specific to developing thymocytes. Studies of mature T cells recovered from spleens of ADA(-/-) mice revealed that ADA deficiency is accompanied by TCR activation defects of T cells in vivo. Furthermore, ex vivo experiments on ADA(-/-) T cells demonstrated that elevated adenosine is responsible for this abnormal TCR signaling. These findings suggest that the metabolic disturbances seen in ADA(-/-) mice affect various signaling pathways that regulate thymocyte survival and function. Experiments with thymocytes ex vivo confirmed that ADA deficiency reduces tyrosine phosphorylation of TCR-associated signaling molecules and blocks TCR-triggered calcium increases.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine / pharmacology
  • Adenosine Deaminase / deficiency*
  • Animals
  • Antigens, CD / biosynthesis
  • Antigens, CD / genetics
  • Antigens, Differentiation, T-Lymphocyte / biosynthesis
  • Antigens, Differentiation, T-Lymphocyte / genetics
  • Apoptosis
  • B-Lymphocytes / pathology
  • Calcium Signaling
  • Cell Differentiation
  • Cells, Cultured
  • Deoxyadenine Nucleotides / metabolism
  • Deoxyadenosines / pharmacology
  • Gene Expression Regulation
  • Lectins, C-Type
  • Lymph Nodes / immunology
  • Lymph Nodes / pathology
  • Lymphocyte Activation
  • Mice
  • Mice, Knockout
  • Mice, SCID
  • Organ Specificity
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Receptor-CD3 Complex, Antigen, T-Cell / immunology*
  • Receptor-CD3 Complex, Antigen, T-Cell / metabolism
  • Receptors, Interleukin-2 / biosynthesis
  • Receptors, Interleukin-2 / genetics
  • Severe Combined Immunodeficiency / genetics
  • Severe Combined Immunodeficiency / immunology
  • Severe Combined Immunodeficiency / pathology*
  • Signal Transduction*
  • Specific Pathogen-Free Organisms
  • Spleen / immunology
  • Spleen / pathology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology*
  • Thymus Gland / drug effects
  • Thymus Gland / pathology*

Substances

  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD69 antigen
  • Deoxyadenine Nucleotides
  • Deoxyadenosines
  • Lectins, C-Type
  • Receptor-CD3 Complex, Antigen, T-Cell
  • Receptors, Interleukin-2
  • Adenosine Deaminase
  • Adenosine
  • 2'-deoxyadenosine triphosphate
  • 2'-deoxyadenosine