title: Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID.
abstract: Adenosine acts as anti-inflammatory mediator on the immune system and has been described in regulatory T cell (Treg)-mediated suppression. In the absence of adenosine deaminase (ADA), adenosine and other purine metabolites accumulate, leading to severe immunodeficiency with recurrent infections (ADA-SCID). Particularly ADA-deficient patients with late-onset forms and after enzyme replacement therapy (PEG-ADA) are known to manifest immune dysregulation. Herein we provide evidence that alterations in the purine metabolism interfere with Treg function, thereby contributing to autoimmune manifestations in ADA deficiency. Tregs isolated from PEG-ADA-treated patients are reduced in number and show decreased suppressive activity, whereas they are corrected after gene therapy. Untreated murine ADA(-/-) Tregs show alterations in the plasma membrane CD39/CD73 ectonucleotidase machinery and limited suppressive activity via extracellular adenosine. PEG-ADA-treated mice developed multiple autoantibodies and hypothyroidism in contrast to mice treated with bone marrow transplantation or gene therapy. Tregs isolated from PEG-ADA-treated mice lacked suppressive activity, suggesting that this treatment interferes with Treg functionality. The alterations in the CD39/CD73 adenosinergic machinery and loss of function in ADA-deficient Tregs provide new insights into a predisposition to autoimmunity and the underlying mechanisms causing defective peripheral tolerance in ADA-SCID.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Via Olgettina 58, Milan, Italy
authors.forename: Aisha V
authors.initials: AV
authors.lastname: Sauer
authors.forename: Immacolata
authors.initials: I
authors.lastname: Brigida
authors.forename: Nicola
authors.initials: N
authors.lastname: Carriglio
authors.forename: Raisa Jofra
authors.initials: RJ
authors.lastname: Hernandez
authors.forename: Samantha
authors.initials: S
authors.lastname: Scaramuzza
authors.forename: Daniela
authors.initials: D
authors.lastname: Clavenna
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanvito
authors.forename: Pietro L
authors.initials: PL
authors.lastname: Poliani
authors.forename: Nicola
authors.initials: N
authors.lastname: Gagliani
authors.forename: Filippo
authors.initials: F
authors.lastname: Carlucci
authors.forename: Antonella
authors.initials: A
authors.lastname: Tabucchi
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Traggiai
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
mesh_terms: D015720:5'-Nucleotidase / Q000276:immunology* / Q000378:metabolism; D000241:Adenosine / Q000276:immunology* / Q000378:metabolism; D000243:Adenosine Deaminase / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000361:Agammaglobulinemia / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D000818:Animals; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D001081:Apyrase / Q000276:immunology* / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D007037:Hypothyroidism / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011092:Polyethylene Glycols / Q000737:chemistry; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D001323:Autoantibodies; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D011092:Polyethylene Glycols; D015720:5'-Nucleotidase; D000243:Adenosine Deaminase; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine