Catalytically active holo Homo sapiens adenosine deaminase I adopts a closed conformation

2022 ◽  
Vol 78 (1) ◽  
Author(s):  
Minh Thu Ma ◽  
Maria Rain Jennings ◽  
John Blazeck ◽  
Raquel L. Lieberman
Keyword(s):  
Adenosine Deaminase ◽  
T Cell Activation ◽  
Cell Activation ◽  
Catalytic Mechanism ◽  
Biochemical Characterization ◽  
Bos Taurus ◽  
Homo Sapiens ◽  
Severe Combined Immunodeficiency ◽  
Closed Conformation ◽  
Catalytically Active

Homo sapiens adenosine deaminase 1 (HsADA1; UniProt P00813) is an immunologically relevant enzyme with roles in T-cell activation and modulation of adenosine metabolism and signaling. Patients with genetic deficiency in HsADA1 suffer from severe combined immunodeficiency, and HsADA1 is a therapeutic target in hairy cell leukemias. Historically, insights into the catalytic mechanism and the structural attributes of HsADA1 have been derived from studies of its homologs from Bos taurus (BtADA) and Mus musculus (MmADA). Here, the structure of holo HsADA1 is presented, as well as biochemical characterization that confirms its high activity and shows that it is active across a broad pH range. Structurally, holo HsADA1 adopts a closed conformation distinct from the open conformation of holo BtADA. Comparison of holo HsADA1 and MmADA reveals that MmADA also adopts a closed conformation. These findings challenge previous assumptions gleaned from BtADA regarding the conformation of HsADA1 that may be relevant to its immunological interactions, particularly its ability to bind adenosine receptors. From a broader perspective, the structural analysis of HsADA1 presents a cautionary tale for reliance on homologs to make structural inferences relevant to applications such as protein engineering or drug development.

scholarly journals Anti-CD3ε mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn syndrome: therapeutic implications

Blood ◽  
2012 ◽  
Vol 120 (5) ◽  
pp. 1005-1014 ◽  
Author(s):  
Veronica Marrella ◽  
Pietro L. Poliani ◽  
Elena Fontana ◽  
Anna Casati ◽  
Virginia Maina ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
T Cell Activation ◽  
Cell Activation ◽  
Severe Combined Immunodeficiency ◽  
Cell Receptor ◽  
Omenn Syndrome ◽  
Activated T Cells ◽  
Therapeutic Implications ◽  
Autoimmune Regulator

Abstract Omenn syndrome (OS) is an atypical primary immunodeficiency characterized by severe autoimmunity because of activated T cells infiltrating target organs. The impaired recombinase activity in OS severely affects expression of the pre-T-cell receptor complex in immature thymocytes, which is crucial for an efficient development of the thymic epithelial component. Anti-CD3ε monoclonal antibody (mAb) treatment in RAG2−/− mice was previously shown to mimic pre-TCR signaling promoting thymic expansion. Here we show the effect of anti-CD3ε mAb administration in the RAG2R229Q mouse model, which closely recapitulates human OS. These animals, in spite of the inability to induce the autoimmune regulator, displayed a significant amelioration in thymic epithelial compartment and an important reduction of peripheral T-cell activation and tissue infiltration. Furthermore, by injecting a high number of RAG2R229Q progenitors into RAG2−/− animals previously conditioned with anti-CD3ε mAb, we detected autoimmune regulator expression together with the absence of peripheral immunopathology. These observations indicate that improving epithelial thymic function might ameliorate the detrimental behavior of the cell-autonomous RAG defect. Our data provide important therapeutic proof of concept for future clinical applications of anti-CD3ε mAb treatment in severe combined immunodeficiency forms characterized by poor thymus function and autoimmunity.

scholarly journals Dendritic cell-expressed common gamma-chain recruits IL-15 for trans-presentation at the murine immunological synapse

2018 ◽  
Vol 3 ◽  
pp. 84 ◽  
Author(s):  
Chiara Beilin ◽  
Kaushik Choudhuri ◽  
Gerben Bouma ◽  
Dessislava Malinova ◽  
Jaime Llodra ◽  
...  
Keyword(s):  
T Cell ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Nk Cell ◽  
Severe Combined Immunodeficiency ◽  
Cd4 T Cell ◽  
Gamma Chain

Background:Mutations of the common cytokine receptor gamma chain (γc) cause Severe Combined Immunodeficiency characterized by absent T and NK cell development. Although stem cell therapy restores these lineages, residual immune defects are observed that may result from selective persistence of γc-deficiency in myeloid lineages. However, little is known about the contribution of myeloid-expressed γc to protective immune responses.  Here we examine the importance of γc for myeloid dendritic cell (DC) function.Methods:We utilize a combination ofin vitroDC/T-cell co-culture assays and a novel lipid bilayer system mimicking the T cell surface to delineate the role of DC-expressed γc during DC/T-cell interaction.Results:We observed that γc in DC was recruited to the contact interface following MHCII ligation, and promoted IL-15Rα colocalization with engaged MHCII. Unexpectedly, trans-presentation of IL-15 was required for optimal CD4+T cell activation by DC and depended on DC γc expression. Neither recruitment of IL-15Rα nor IL-15 trans-signaling at the DC immune synapse (IS), required γc signaling in DC, suggesting that γc facilitates IL-15 transpresentation through induced intermolecularcisassociations or cytoskeletal reorganization following MHCII ligation.Conclusions:These findings show that DC-expressed γc is required for effective antigen-induced CD4+ T cell activation. We reveal a novel mechanism for recruitment of DC IL-15/IL-15Rα complexes to the IS, leading to CD4+ T cell costimulation through localized IL-15 transpresentation that is coordinated with antigen-recognition.

Influence of adenosine deaminase inhibition on the phosphoinositide turnover in the initial stages of human T cell activation

1990 ◽  
Vol 20 (3) ◽  
pp. 611-615 ◽  
Author(s):  
Hélène A. Buc ◽  
Arlette Moncion ◽  
Michèle Hamet ◽  
Anne-Marie Houllier ◽  
Laure Thuilier ◽  
...  
Keyword(s):  
T Cell ◽  
Adenosine Deaminase ◽  
T Cell Activation ◽  
Cell Activation ◽  
Phosphoinositide Turnover ◽  
Human T Cell

scholarly journals Correction: Levels of Adenosine Deaminase on Dendritic Cells Promote Autoreactive T Cell Activation and Diabetes in Nonobese Diabetic Mice

2011 ◽  
Vol 187 (4) ◽  
pp. 2031-2031
Author(s):  
Faranak Ghaemi Oskouie ◽  
Afshin Shameli ◽  
Ailian Yang ◽  
Melanie D. Desrosiers ◽  
Ashley D. Mucsi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Adenosine Deaminase ◽  
T Cell Activation ◽  
Cell Activation ◽  
Diabetic Mice ◽  
Nonobese Diabetic ◽  
Autoreactive T Cell ◽  
Nonobese Diabetic Mice

scholarly journals Serum Adenosine Deaminase Activity in Monitoring Disease Activity and Response to Therapy in Severe Psoriasis

2006 ◽  
Vol 49 (2) ◽  
pp. 101-104 ◽  
Author(s):  
Zülal Erbagci ◽  
A. Binnur Erbagci ◽  
Oya Köylüoglu ◽  
A. Almila Tuncel
Keyword(s):  
Disease Activity ◽  
Adenosine Deaminase ◽  
T Cell Activation ◽  
Cell Activation ◽  
Clinical Findings ◽  
Severe Psoriasis ◽  
Response To Therapy ◽  
Group I ◽  
Adenosine Deaminase Activity ◽  
Group Ii

Objectives: Activity of Serum Adenosine Deaminase (ADA), a main enzyme in purine degradation and considered as a marker for non-specific T cell activation, in psoriasis has been investigated in a few studies with conflicting results. Design and Methods: To evaluate the significance of serum ADA activity in psoriasis, and analyze whether ADA activity may be related to disease activity, we performed a prospective study with 38 cases of psoriasis and 24 healthy volunteers. Patients were divided into two groups as cases with local and stable lesions (Group i, n: 20) and severe cases with extensive involvement (Group ii, n: 18). Serum ADA activity was determined by modified Guisti procedure. Results: When taken into consideration of all patients -regardless of the severity of the disease- the mean serum ADA activity of psoriatics did not differ significantly from that of controls (p>0.05). However, it was higher in Group ii than in Group i and healthy controls (respectively p<0.001 and p<0.05). A significant decrease was observed also after therapy only in Group ii (p<0.001). Conclusion: Serum ADA activity may be correlated to the disease activity of severe psoriasis. We suggest that it might be a serologic marker for follow-up of in such cases. It could be used in predicting relapses before clinical findings as well as in deciding to stop or decrease systemic therapies at the right time, which have potential to cause severe systemic side effects when given for a long period. Further studies with larger case populations are required to support our findings.

scholarly journals Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients

Blood ◽  
2008 ◽  
Vol 111 (8) ◽  
pp. 4209-4219 ◽  
Author(s):  
Barbara Cassani ◽  
Massimiliano Mirolo ◽  
Federica Cattaneo ◽  
Ulrike Benninghoff ◽  
Michael Hershfield ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Severe Combined Immunodeficiency ◽  
A2a Adenosine Receptor ◽  
Hematopoietic Stem ◽  
Protein Levels ◽  
Cell Functions

Abstract Mutations in the adenosine deaminase (ADA) gene are responsible for a form of severe combined immunodeficiency (SCID) caused by the lymphotoxic accumulation of ADA substrates, adenosine and 2′-deoxy-adenosine. The molecular mechanisms underlying T-cell dysfunction in humans remain to be elucidated. Here, we show that CD4+ T cells from ADA-SCID patients have severely compromised TCR/CD28-driven proliferation and cytokine production, both at the transcriptional and protein levels. Such an impairment is associated with an intrinsically reduced ZAP-70 phosphorylation, Ca2+ flux, and ERK1/2 signaling and to defective transcriptional events linked to CREB and NF-κB. Moreover, exposure to 2′-deoxy-adenosine results in a stronger inhibition of T-cell activation, mediated by the aberrant A2A adenosine receptor signaling engagement and PKA hyperactivation, or in a direct apoptotic effect at higher doses. Conversely, in T cells isolated from patients after gene therapy with retrovirally transduced hematopoietic stem/progenitor cells, the biochemical events after TCR triggering occur properly, leading to restored effector functions and normal sensitivity to apoptosis. Overall, our findings provide a better understanding of the pathogenesis of the immune defects associated with an altered purine metabolism and confirm that ADA gene transfer is an efficacious treatment for ADA-SCID. The trials in this study are enrolled at www.ClinicalTrials.gov as #NCT00598481 and #NCT0059978.

scholarly journals Dendritic cell-expressed common gamma-chain recruits IL-15 for trans-presentation at the murine immunological synapse

2018 ◽  
Vol 3 ◽  
pp. 84 ◽  
Author(s):  
Chiara Beilin ◽  
Kaushik Choudhuri ◽  
Gerben Bouma ◽  
Dessislava Malinova ◽  
Jaime Llodra ◽  
...  
Keyword(s):  
T Cell ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Nk Cell ◽  
Severe Combined Immunodeficiency ◽  
Cd4 T Cell ◽  
Gamma Chain

Background:Mutations of the common cytokine receptor gamma chain (γc) cause Severe Combined Immunodeficiency characterized by absent T and NK cell development. Although stem cell therapy restores these lineages, residual immune defects are observed that may result from selective persistence of γc-deficiency in myeloid lineages. However, little is known about the contribution of myeloid-expressed γc to protective immune responses.  Here we examine the importance of γc for myeloid dendritic cell (DC) function.Methods:We utilize a combination ofin vitroDC/T-cell co-culture assays and a novel lipid bilayer system mimicking the T cell surface to delineate the role of DC-expressed γc during DC/T-cell interaction.Results:We observed that γc in DC was recruited to the contact interface following MHCII ligation, and promoted IL-15Rα colocalization with engaged MHCII. Unexpectedly, trans-presentation of IL-15 was required for optimal CD4+T cell activation by DC and depended on DC γc expression. Neither recruitment of IL-15Rα nor IL-15 trans-signaling at the DC immune synapse (IS), required γc signaling in DC, suggesting that γc facilitates IL-15 transpresentation through induced intermolecularcisassociations or cytoskeletal reorganization following MHCII ligation.Conclusions:These findings show that DC-expressed γc is required for effective antigen-induced CD4+ T cell activation. We reveal a novel mechanism for recruitment of DC IL-15/IL-15Rα complexes to the IS, leading to CD4+ T cell costimulation through localized IL-15 transpresentation that is coordinated with antigen-recognition.

scholarly journals High Levels of Adenosine Deaminase on Dendritic Cells Promote Autoreactive T Cell Activation and Diabetes in Nonobese Diabetic Mice

2011 ◽  
Vol 186 (12) ◽  
pp. 6798-6806 ◽  
Author(s):  
Faranak Ghaemi Oskouie ◽  
Afshin Shameli ◽  
Ailian Yang ◽  
Melanie D. Desrosiers ◽  
Ashley D. Mucsi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Adenosine Deaminase ◽  
T Cell Activation ◽  
Cell Activation ◽  
Diabetic Mice ◽  
Nonobese Diabetic ◽  
Autoreactive T Cell ◽  
Nonobese Diabetic Mice
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