Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling.
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.
Apasov
S G
SG
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892, USA.
Blackburn
M R
MR
Kellems
R E
RE
Smith
P T
PT
Sitkovsky
M V
MV
D000241:Adenosine / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000172:deficiency*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics; D017209:Apoptosis; D001402:B-Lymphocytes / Q000473:pathology; D020013:Calcium Signaling; D002454:Cell Differentiation; D002478:Cells, Cultured; D003838:Deoxyadenine Nucleotides / Q000378:metabolism; D003839:Deoxyadenosines / Q000494:pharmacology; D005786:Gene Expression Regulation; D037181:Lectins, C-Type; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009928:Organ Specificity; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology*; D000099192:CD69 Antigens
D000241:Adenosine; D000243:Adenosine Deaminase; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D003838:Deoxyadenine Nucleotides; D003839:Deoxyadenosines; D037181:Lectins, C-Type; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D000099192:CD69 Antigens; C026600:2'-deoxyadenosine triphosphate; C058118:2'-deoxyadenosine