NKG2A inhibits NKG2C effector functions of γδ T cells: implications in health and disease

Angelini, Daniela F.; Zambello, Renato; Galandrini, Ricciarda; Diamantini, Adamo; Placido, Roberta; Micucci, Federica; Poccia, Fabrizio; Semenzato, G.; Borsellino, Giovanna; Santoni, Angela; Battistini, Luca

doi:10.1189/jlb.0710413

Cited by 38 publications

(36 citation statements)

References 56 publications

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“…Similar to a previous study [20], the fraction of NKG2C + γδ + T cells varied widely in all groups of this study. However, a slight increase of activating NKG2C + γδ + T cells among the PB lymphocytes was observed in the BD group compared to the HC (0.5 vs. 0.3%, P = 0.008).…”

Section: Resultssupporting

confidence: 86%

“…CD94/NKG2C complex is functional with IFN-γ production, T cell proliferation and cytolytic activity, whereas NKG2A expression was found on all γδ T cell memory subsets, suggesting a crucial role of the inhibitory signal provided by this receptor on γδ T cell responses [20]. In BD and in A-BD a slight increase of activating NKG2C + γδ T cells has been detected showing an activation status of the cells, although the other activating receptor, NKG2D, was decreased in BD.…”

Section: Discussionmentioning

confidence: 99%

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Expression of regulatory receptors on γδ T Cells and their cytokine production in Behcet's disease

et al. 2013

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IntroductionBehcet's disease (BD) is a multi-systemic disorder with muco-cutaneous, ocular, arthritic, vascular or central nervous system involvement. The role of γδ T cells is implicated in BD. The activation status of γδ T cells and their cytokine secretion against phosphoantigens are evaluated in BD.MethodsNKG2A, NKG2C, NKG2D, CD16 and CCR7 molecules on γδ T cells were analyzed in 70 BD, 27 tuberculosis (TB) patients and 26 healthy controls (HC). Peripheral γδ T cells were expanded with a phosphoantigen (BrHPP) and IL-2, restimulated with BrHPP and a TLR3 ligand, and cytokine production was measured.Resultsγδ T cells were not increased in both BD and TB patients, but the proportions of TCRVδ2+ T cells were lower (58.9 and 50.7 vs. 71.7%, P = 0.04 and P = 0.005) compared to HC. Higher proportion of TCRVδ2+ T cells were CD16+ (26.2 and 33.9 vs. 16.6%, P = 0.02 and P = 0.001) and CCR7- (32.2 and 27.9 vs. 17.7%, P < 0.0001 and P = 0.014) in BD and TB patients compared to HC. NKG2C+ γδ+ T cells were relatively increased (0.5 and 0.6 vs. 0.3%, P = 0.008 and 0.018), whereas NKG2D positivity was decreased in patients with BD and TB (77.7 and 75.8 vs. 87.5%, P = 0.001 and 0.004). Expansion capacity of γδ T cells in BD and TB as well as production of IL-13, IFN-γ, granulocyte monocyte colony stimulating factor (GM-CSF), TNF-α, CCL4 and CCL5 in BD was lower compared to HC, when restimulated by TLR3 ligand and BrHPP.ConclusionThe changes on γδ T cells of BD as well as TB patients implicate that γδ T cells have already been exposed to regulatory effects, which changed their activity. Lower cytokine response of γδ T cells implicates down modulation of these cells in BD.

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Section: Resultssupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Expression of regulatory receptors on γδ T Cells and their cytokine production in Behcet's disease

et al. 2013

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“…As reviewed, NKG2A, an inhibitory receptor expressed by NK cells and CD8 + T cells, plays an important role in HIV, HCV [38], [39], and HBV [40] infections. NKG2A also mediates suppressive signaling in human γδ T cells [16], [41]. In the current study, we found that most γδ DNT cells expressed NKG2A, and the frequency of HLA-E in CD8 + αβ T cells was higher in patients with CHB.…”

Section: Discussionsupporting

confidence: 56%

TCRγδ+CD4−CD8− T Cells Suppress the CD8+ T-Cell Response to Hepatitis B Virus Peptides, and Are Associated with Viral Control in Chronic Hepatitis B

Lai

et al. 2014

PLoS ONE

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The immune mechanisms underlying failure to achieve hepatitis B e antigen (HBeAg) seroconversion associated with viral control in chronic hepatitis B (CHB) remain unclear. Here we investigated the role of CD4−CD8− T (double-negative T; DNT) cells including TCRαβ+ DNT (αβ DNT) and TCRγδ+ DNT (γδ DNT) cells. Frequencies of circulating DNT cell subsets were measured by flow cytometry in a retrospective cohort of 51 telbivudine-treated HBeAg-positive CHB patients, 25 immune tolerant carriers (IT), 33 inactive carriers (IC), and 37 healthy controls (HC). We found that γδ DNT cell frequencies did not significantly change during treatment, being lower at baseline (P = 0.019) in patients with HBeAg seroconversion after 52 weeks of antiviral therapy (n = 20) than in those without (n = 31), and higher in the total CHB and IT than IC and HC groups (P<0.001). αβ DNT cell frequencies were similar for all groups. In vitro, γδ DNT cells suppressed HBV core peptide-stimulated interferon-γ and tumor necrosis factor-α production in TCRαβ+CD8+ T cells, which may require cell–cell contact, and could be partially reversed by anti-NKG2A. These findings suggest that γδ DNT cells limit CD8+ T cell response to HBV, and may impede HBeAg seroconversion in CHB.

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“…The cytolytic function of γδ T cells is tightly regulated by receptors such as NKG2A, NKG2D and NKG2C (50, 51). HIV/SIV infection activates γδ T cells as shown here by the increase in CD69 + γδ T cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mucosal and Systemic γδ+ T Cells Associated with Control of Simian Immunodeficiency Virus Infection

Tuero

Venzon

Robert-Guroff

2016

The Journal of Immunology

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γδ T cells act as a first line of defense against invading pathogens. However, despite their abundance in mucosal tissue, little information is available about their functionality in this compartment in the context of HIV/SIV infection. Here we evaluated the frequency, phenotype and functionality of Vδ1 and Vδ2 T cells from blood, rectum, and the female reproductive tract (FRT) of Rhesus macaques to determine whether these cells contribute to control of SIV infection. No alteration in the peripheral Vδ1/Vδ2 ratio in SIV-infected macaques was observed. However, CD8+ and CD4+CD8+Vδ1 T cells were expanded along with upregulation of NKG2D, CD107, and Granzyme B (Grz B), suggesting cytotoxic function. In contrast, Vδ2 T cells showed a reduced ability to produce the inflammatory cytokine IFN-γ. In the FRT of SIV+ macaques Vδ1 and Vδ2 showed comparable levels across vaginal, ectocervical and endocervical tissues, however endocervical Vδ2 T cells showed higher inflammatory profiles than the two other regions. No sex difference was seen in the rectal Vδ1/Vδ2 ratio. Several peripheral Vδ1 and/or Vδ2 T cell subpopulations expressing IFN-γ, and/or NKG2D were positively correlated with decreased plasma viremia. Notably, Vδ2 CD8+ T cells of the endocervix were negatively correlated with chronic viremia. Overall our results suggest that a robust Vδ1 and Vδ2 T cell response in blood and the FRT of SIV-infected macaques contributes to control of viremia.

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NKG2A inhibits NKG2C effector functions of γδ T cells: implications in health and disease

Cited by 38 publications

References 56 publications

Expression of regulatory receptors on γδ T Cells and their cytokine production in Behcet's disease

Expression of regulatory receptors on γδ T Cells and their cytokine production in Behcet's disease

TCRγδ+CD4−CD8− T Cells Suppress the CD8+ T-Cell Response to Hepatitis B Virus Peptides, and Are Associated with Viral Control in Chronic Hepatitis B

Mucosal and Systemic γδ+ T Cells Associated with Control of Simian Immunodeficiency Virus Infection

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