Decreased frequency of CD73+CD8+ T cells of HIV-infected patients correlates with immune activation and T cell exhaustion

Tóth, Ilona; Le, Anh Q.; Hartjen, Philip; Thomssen, Adriana; Matzat, V; Lehmann, Clara; Scheurich, C; Beisel, Claudia; Busch, Philipp; Degen, Olaf; Lohse, Ansgar W.; Eiermann, Thomas; Fätkenheuer, Gerd; Meyer-Olson, Dirk; Bockhorn, Maximilian; Hauber, Joachim; Lunzen, Jan van; Wiesch, Julian Schulze zur

doi:10.1189/jlb.0113018

Cited by 59 publications

(68 citation statements)

References 63 publications

(64 reference statements)

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“…These findings corroborate reports showing a strong correlation between downregulation of CD73 expression on CD8 ϩ T cells and high levels of immune activation in HIV-infected patients (48). Altogether, these seminal studies point to a previously unrecognized functional role of the ADO pathway in modulating HIV-1-associated immune activation.…”

Section: Discussionsupporting

confidence: 80%

“…While murine Tregs coexpress CD39 and CD73 (34,79), few human circulating CD4 ϩ T cells coexpress both ectoenzymes. Only one prior study (48) reported increased CD39/CD73 coexpression on T cells isolated from LNs from HIV patients. This prompted us to assess the frequency of the coexpression of these ADO production markers in order to more extensively characterize this pathway.…”

Section: Discussionmentioning

confidence: 99%

“…CD4 ϩ CD73 ϩ T cells are depleted in HIV-1-infected patients regardless of viral suppression (47), while peripheral CD73-expressing CD8 ϩ T cells from HIV-infected patients can be partially reversed by antiretroviral therapy (ART) (48). Notably, the vast majority of these studies focused on T cells from peripheral blood.…”

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confidence: 99%

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Critical Role for the Adenosine Pathway in Controlling Simian Immunodeficiency Virus-Related Immune Activation and Inflammation in Gut Mucosal Tissues

Brocca-Cofano

Gillespie

et al. 2015

J Virol

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The role of the adenosine (ADO) pathway in human immunodeficiency virus type 1/simian immunodeficiency virus (HIV-1/ SIV) infection remains unclear. We compared SIVsab-induced changes of markers related to ADO production (CD39 and CD73) and breakdown (CD26 and adenosine deaminase) on T cells from blood, lymph nodes, and intestine collected from pigtailed macaques (PTMs) and African green monkeys (AGMs) that experience different SIVsab infection outcomes. We also measured ADO and inosine (INO) levels in tissues by mass spectrometry. Finally, we assessed the suppressive effect of ADO on proinflammatory cytokine production after T cell receptor stimulation. The baseline level of both CD39 and CD73 coexpression on regulatory T cells and ADO levels were higher in AGMs than in PTMs. Conversely, high INO levels associated with dramatic increases in CD26 expression and adenosine deaminase activity were observed in PTMs during chronic SIV infection. Immune activation and inflammation markers in the gut and periphery inversely correlated with ADO and directly correlated with INO. Ex vivo administration of ADO significantly suppressed proinflammatory cytokine production by T cells in both species. In conclusion, the opposite dynamics of ADO pathway-related markers and contrasting ADO/INO levels in species with divergent proinflammatory responses to SIV infection support a key role of ADO in controlling immune activation/inflammation in nonprogressive SIV infections. Changes in ADO levels predominately occurred in the gut, suggesting that the ADO pathway may be involved in sparing natural hosts of SIVs from developing SIV-related gut dysfunction. Focusing studies of the ADO pathway on mucosal sites of viral replication is warranted. IMPORTANCEThe mechanisms responsible for the severe gut dysfunction characteristic of progressive HIV and SIV infection in humans and macaques are not completely elucidated. We report that ADO may play a key role in controlling immune activation/inflammation in nonprogressive SIV infections by limiting SIV-related gut inflammation. Conversely, in progressive SIV infection, significant degradation of ADO occurs, possibly due to an early increase of ADO deaminase complexing protein 2 (CD26) and adenosine deaminase. Our study supports therapeutic interventions to offset alterations of this pathway during progressive HIV/SIV infections. These potential approaches to control chronic immune activation and inflammation during pathogenic SIV infection may prevent HIV disease progression.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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Critical Role for the Adenosine Pathway in Controlling Simian Immunodeficiency Virus-Related Immune Activation and Inflammation in Gut Mucosal Tissues

Brocca-Cofano

Gillespie

et al. 2015

J Virol

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“…1 ). In humans, only a small fraction of Tregs express CD73 in steady-state ( 12 ). In response to IL2, however, the majority of human Tregs express both CD39 and CD73 ( 13 ).…”

Section: Adenosine-abundant Tumor Microenvironmentmentioning

confidence: 99%

Targeting Cancer-Derived Adenosine:New Therapeutic Approaches

et al. 2014

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CD73 generation of immunosuppressive adenosine within the hypoxic tumor microenvironment causes dysregulation of immune cell infi ltrates, resulting in tumor progression, metastases, and poor disease outcomes. Therapies targeted toward the adenosinergic pathway, such as antibodies targeting CD73 and CD39, have proven effi cacy in mouse tumor models; however, humanized versions are only in preliminary development. In contrast, A 2A adenosine receptor antagonists have progressed to late-stage clinical trials in Parkinson disease, yet evidence of their role in oncology is limited. This review will compare the merits and challenges of these therapeutic approaches, identifying tumor indications and combinations that may be fruitful as they progress to the clinic.Signifi cance: High concentrations of immunosuppressive adenosine have been reported in cancers, and adenosine is implicated in the growth of tumors. This brief review delineates the current treatment strategies and tumor subtypes that will benefi t from targeting adenosinergic pathways, alone or in combination with contemporary approaches to cancer treatment. Cancer Discov; 4(8);

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“…Recently, a subset of these T follicular cells expressing FoxP3 has been described. This transcription factor defines T regulatory cells, a CD4 T-cell subset that limit effector T-cell response and maintain peripheral tolerance (Ramiscal and Vinuesa 2013) by modulating the dephosphorylation pathway of ATP (Toth 2013). Mice studies have shown that these T follicular regulatory (TFR) cells localize in the B-cell follicles and can regulate humoral immune responses through repressing TFH cells and GC formation.…”

Section: Cd4 T Follicular Cell Subsetsmentioning

confidence: 98%