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
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenosine / pharmacology
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Adenosine Deaminase / deficiency*
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Animals
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Antigens, CD / biosynthesis
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Antigens, CD / genetics
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Antigens, Differentiation, T-Lymphocyte / biosynthesis
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Antigens, Differentiation, T-Lymphocyte / genetics
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Apoptosis
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B-Lymphocytes / pathology
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Calcium Signaling
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Cell Differentiation
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Cells, Cultured
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Deoxyadenine Nucleotides / metabolism
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Deoxyadenosines / pharmacology
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Gene Expression Regulation
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Lectins, C-Type
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Lymph Nodes / immunology
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Lymph Nodes / pathology
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Lymphocyte Activation
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Mice
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Mice, Knockout
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Mice, SCID
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Organ Specificity
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Phosphorylation
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Protein Processing, Post-Translational
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Receptor-CD3 Complex, Antigen, T-Cell / immunology*
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Receptor-CD3 Complex, Antigen, T-Cell / metabolism
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Receptors, Interleukin-2 / biosynthesis
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Receptors, Interleukin-2 / genetics
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Severe Combined Immunodeficiency / genetics
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Severe Combined Immunodeficiency / immunology
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Severe Combined Immunodeficiency / pathology*
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Signal Transduction*
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Specific Pathogen-Free Organisms
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Spleen / immunology
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Spleen / pathology
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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T-Lymphocytes / pathology*
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Thymus Gland / drug effects
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Thymus Gland / pathology*
Substances
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Antigens, CD
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Antigens, Differentiation, T-Lymphocyte
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CD69 antigen
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Deoxyadenine Nucleotides
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Deoxyadenosines
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Lectins, C-Type
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Receptor-CD3 Complex, Antigen, T-Cell
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Receptors, Interleukin-2
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Adenosine Deaminase
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Adenosine
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2'-deoxyadenosine triphosphate
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2'-deoxyadenosine