Adenosine regulates CD8 T‐cell priming by inhibition of membrane‐proximal T‐cell receptor signalling

Linnemann, Carsten; Schildberg, Frank A.; Schurich, Anna; Diehl, Linda; Hegenbarth, Silke; Endl, Elmar; Lacher, Svenja; Müller, Christian; Frey, Jürgen; Simeoni, Luca; Schraven, Burkhart; Stabenow, Dirk; Knolle, Percy A.

doi:10.1111/j.1365-2567.2009.03075.x

Cited by 97 publications

(95 citation statements)

References 57 publications

(117 reference statements)

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“…It is also known that adenosine prevents the priming of naïve CD8 cytotoxic T cells [26] by antigen-presenting cells. In our study, IgG deposition in the glomeruli was associated with the presence of CD25+activated CD8+T cells.…”

Section: Discussionmentioning

confidence: 99%

Autoimmunity in CD73/Ecto-5′-Nucleotidase Deficient Mice Induces Renal Injury

et al. 2012

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Extracellular adenosine formed by 5′-ectonucleotidase (CD73) is involved in tubulo-glomerular feedback in the kidney but is also known to be an important immune modulator. Since CD73−/−mutant mice exhibit a vascular proinflammatory phenotype, we asked whether long term lack of CD73 causes inflammation related kidney pathologies. CD73−/−mice (13 weeks old) showed significantly increased low molecule proteinuria compared to C57BL6 wild type controls (4.8≥0.52 vs. 2.9±0.54 mg/24 h, p<0.03). Total proteinuria increased to 5.97±0.78 vs. 2.55±0.35 mg/24 h at 30 weeks (p<0.01) whereas creatinine clearance decreased (0.161±0.02 vs. 0.224±0.02 ml/min). We observed autoimmune inflammation in CD73−/−mice with glomerulitis and peritubular capillaritis, showing glomerular deposition of IgG and C3 and enhanced presence of CD11b, CD8, CD25 as well as GR-1-positive cells in the interstitium. Vascular inflammation was associated with enhanced serum levels of the cytokines IL-18 and TNF-α as well as VEGF and the chemokine MIP-2 (CXCL-2) in CD73−/−mice, whereas chemokines and cytokines in the kidney tissue were unaltered or reduced. In CD73−/−mice glomeruli, we found a reduced number of podocytes and endothelial fenestrations, increased capillaries per glomeruli, endotheliosis and enhanced tubular fibrosis. Our results show that adult CD73−/−mice exhibit spontaneous proteinuria and renal functional deterioration even without exogenous stress factors. We have identified an autoimmune inflammatory phenotype comprising the glomerular endothelium, leading to glomeruli inflammation and injury and to a cellular infiltrate of the renal interstitium. Thus, long term lack of CD73 reduced renal function and is associated with autoimmune inflammation.

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Section: Discussionmentioning

confidence: 99%

Autoimmunity in CD73/Ecto-5′-Nucleotidase Deficient Mice Induces Renal Injury

et al. 2012

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“…27,28 Adenosine, which is present at increased concentrations in cancer tissue, 29,30 has a crucial role in the activity alteration of immune cells including Tregs 31 and CD8 C T cells. 32 We found that a large fraction of CD39 C gdT cells co-expressed CD73 (Fig. 4A).…”

Section: Tumor-infiltrating Cd39 C Gdt Cells Have Potent Immunosupprementioning

confidence: 95%

Tumor-infiltrating CD39⁺γδTregs are novel immunosuppressive T cells in human colorectal cancer

Cheng

et al. 2017

OncoImmunology

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Tumor microenvironment (TME) promotes immune suppression through recruiting and expanding suppressive immune cells such as regulatory T cells (Tregs) to facilitate cancer progression. In this study, we identify a novel CD39 C gdTreg in human colorectal cancer (CRC). CD39 C gdTregs are the predominant regulatory T cells and have more potent immunosuppressive activity than CD4 C or CD8 C Tregs via the adenosine-mediated pathway but independent of TGF-b or IL-10. They also secrete cytokines including IL-17A and GM-CSF, which may chemoattract myeloid-derived suppressive cells (MDSCs), thus establishing an immunosuppressive network. We further demonstrate that tumor-derived TGF-b1 induces CD39 C gdT cells from paired normal colon tissues to produce more adenosine and become potent immunosuppressive T cells. Moreover, CD39 C gdTreg infiltration is positively correlated with TNM stage and other unfavorable clinicopathological features, implicating that CD39 C gdTregs are one of the key players in establishment of immunosuppressive TME in human CRC that may be critical for tumor immunotherapy.

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“…47,48 Additionally, stimulation of A 2A adenosine receptors suppresses the production of interferon-γ (IFN-γ) and IL-4 by both naive CD4 + T cells and polarized type 1 T helper (T H ) cells and T H 2 cells. 11,47,49,50 Similarly, adenosine suppresses the activity of naive CD8 + T cells 51 and controls the effector functions of fully differentiated CD8 + T cells. 49,52,53 However, the role of adenosine in regulating T cell functions at onset of T1DM is incompletely understood.…”

Section: Immune Cellsmentioning

confidence: 98%

Adenosine signalling in diabetes mellitus—pathophysiology and therapeutic considerations

et al. 2015

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Adenosine is a key extracellular signalling molecule that regulates several aspects of tissue function by activating four G-protein-coupled receptors, A1, A2A, A2B and A1 adenosine receptors. Accumulating evidence highlights a critical role for the adenosine system in the regulation of glucose homeostasis and the pathophysiology of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Although adenosine signalling is known to affect insulin secretion, new data indicate that adenosine signalling also contributes to the regulation of β-cell homeostasis and activity by controlling the proliferation and regeneration of these cells as well as the survival of β cells in inflammatory microenvironments. Furthermore, adenosine is emerging as a major regulator of insulin responsiveness by controlling insulin signalling in adipose tissue, muscle and liver; adenosine also indirectly mediates effects on inflammatory and/or immune cells in these tissues. This Review critically discusses the role of the adenosine-adenosine receptor system in regulating both the onset and progression of T1DM and T2DM, and the potential of pharmacological manipulation of the adenosinergic system as an approach to manage T1DM, T2DM and their associated complications.

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Adenosine regulates CD8 T‐cell priming by inhibition of membrane‐proximal T‐cell receptor signalling

Cited by 97 publications

References 57 publications

Autoimmunity in CD73/Ecto-5′-Nucleotidase Deficient Mice Induces Renal Injury

Autoimmunity in CD73/Ecto-5′-Nucleotidase Deficient Mice Induces Renal Injury

Tumor-infiltrating CD39⁺γδTregs are novel immunosuppressive T cells in human colorectal cancer

Adenosine signalling in diabetes mellitus—pathophysiology and therapeutic considerations

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Adenosine regulates CD8 T‐cell priming by inhibition of membrane‐proximal T‐cell receptor signalling

Cited by 97 publications

References 57 publications

Autoimmunity in CD73/Ecto-5′-Nucleotidase Deficient Mice Induces Renal Injury

Autoimmunity in CD73/Ecto-5′-Nucleotidase Deficient Mice Induces Renal Injury

Tumor-infiltrating CD39+γδTregs are novel immunosuppressive T cells in human colorectal cancer

Adenosine signalling in diabetes mellitus—pathophysiology and therapeutic considerations

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Tumor-infiltrating CD39⁺γδTregs are novel immunosuppressive T cells in human colorectal cancer