Characterization of KIR + NKG2A + Eomes− NK‐like CD8+ T cells and their decline with age in healthy individuals

Kasakovski, Dimitri; Zeng, Xiangbo; Lai, Jing; Yu, Zhi; Yao, Danlin; Chen, Shaohua; Zha, Xianfeng; Li, Yangqiu; Xu, Ling

doi:10.1002/cyto.b.21945

Cited by 9 publications

(8 citation statements)

References 49 publications

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“…Lastly, we documented that this phenomenon preexists in healthy controls. Indeed, frequency of Innate E(+) CD8 T-cells was apparently not related to age, corroborating findings from Kasakovski et al obtained with a larger healthy cohort aged from 6 to 84 years ( 81 ). Moreover, the healthy control Innate E(+) CD8 T-cell population appeared more enriched in senescent cells compared to its conventional memory counterpart, whose senescent phenotype increased with age.…”

Section: Discussionsupporting

confidence: 87%

Allotransplantation Is Associated With Exacerbation of CD8 T-Cell Senescence: The Particular Place of the Innate CD8 T-Cell Component

et al. 2021

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Immunosenescence is a physiological process that is associated with changes in the immune system, particularly among CD8 T-cells. Recent studies have hypothesized that senescent CD8 T-cells are produced with chronologic age by chronic stimulation, leading to the acquisition of hallmarks of innate-like T-cells. While conventional CD8 T-cells are quite well characterized, CD8 T-cells sharing features of NK cells and memory CD8 T-cells, are a newly described immune cell population. They can be distinguished from conventional CD8 T-cells by their combined expression of panKIR/NKG2A and Eomesodermin (E), a unique phenotype closely associated with IFN-γ production in response to innate stimulation. Here, we first provided new evidence in favor of the innate character of panKIR/NKG2A(+) E(+) CD8 T-cells in normal subjects, documenting their position at an intermediate level in the innateness gradient in terms of both innate IFN-γ production and diminished mitochondrial mass. We also revealed that CD8 E(+) panKIR/NKG2A(+) T-cells, hereafter referred to as Innate E(+) CD8 T-cells, exhibit increased senescent (CD27(-) CD28(-)) phenotype, compared to their conventional memory counterparts. Surprisingly, this phenomenon was not dependent on age. Given that inflammation related to chronic viral infection is known to induce NK-like marker expression and a senescence phenotype among CD8 T-cells, we hypothesized that innate E(+) CD8 T-cells will be preferentially associated with exacerbated cellular senescence in response to chronic alloantigen exposure or CMV infection. Accordingly, in a pilot cohort of stable kidney allotransplant recipients, we observed an increased frequency of the Innate E(+) CD8 T-cell subset, together with an exacerbated senescent phenotype. Importantly, this phenotype cannot be explained by age alone, in clear contrast to their conventional memory counterparts. The senescent phenotype in CD8 T-cells was further increased in cytomegalovirus (CMV) positive serology transplant recipients, suggesting that transplantation and CMV, rather than aging by itself, may promote an exacerbated senescent phenotype of innate CD8 T-cells. In conclusion, we proposed that kidney transplantation, via the setting of inflammatory stimuli of alloantigen exposure and CMV infection, may exogenously age the CD8 T-cell compartment, especially its innate component. The physiopathological consequences of this change in the immune system remain to be elucidated.

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Section: Discussionsupporting

confidence: 87%

Allotransplantation Is Associated With Exacerbation of CD8 T-Cell Senescence: The Particular Place of the Innate CD8 T-Cell Component

et al. 2021

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“…Unconventional T cells bridge innate and adaptive immunity, which typically exhibits rapid immune responses, including γδ T cells or our previously described KIR + NKG2A + Eomes − NK‐like CD8 + T cells (Bagwell, 2021; Kasakovski et al, 2021). Included in these T cells are MAIT cells, which have been indicated to be involved in the immunopathology of autoimmune disease (Toubal et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Increased IFN‐γ⁺ and TNF‐α⁺ mucosal‐associated invariant T cells in patients with aplastic anemia

Chen

Zhang

et al. 2023

Cytometry Part B Clinical

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Background Aplastic anemia (AA) is known as an autoimmune disease in which T cell activation is aberrant. It has been reported that unconventional T cells, mucosal‐associated invariant T (MAIT) cells, play an important role in several autoimmune diseases, but it is unclear if they are involved in AA. Methods In this study, we for the first time analyzed the proportions, phenotypes, and cytokine properties of MAIT cells in AA by flow cytometry. Results We found that the percentage of circulating MAIT cells was generally higher for CD3+, CD8+, and CD8− T cells in AA patients compared with healthy individuals. Moreover, the percentage of IL‐18Rα‐, NKG2D‐, IFN‐γ‐, and TNF‐α‐ positive MAIT cells was also significantly higher in AA patients. In addition, the percentage of IFN‐γ+ CD3+ or TNF‐α+CD8− MAIT cells had a significant negative correlation with the absolute neutrophil count. Conclusions We present the first observation of MAIT cells in patients with AA. MAIT cells are associated with a higher frequency of IFN‐γ and TNF‐α production and may contribute to the pathogenesis of AA.

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“…Cell surface staining analysis for PD‐1, Tim‐3, CD244, CD25, CD3, CD4, CD8, and CD45 and intranuclear staining analysis for TOX and FoxP3 were performed with a BD FACS Canto flow cytometer (BD Biosciences, San Jose, USA) and Flowjo software (Flowjo LLC, USA) as previously described (Huang et al, 2021; Kasakovski et al, 2021). The antibodies used for this study were purchased from BD Biosciences (San Jose, USA) and eBioscience (San Diego, USA).…”

Section: Methodsmentioning

confidence: 99%

Increased TOX expression concurrent with PD‐1, Tim‐3, and CD244 expression in T cells from patients with acute myeloid leukemia

Huang

Liang

Zhao

et al. 2021

Cytometry Part B Clinical

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Background T cell dysregulation is a common event in leukemia. Recent findings have indicated that aberrant expression of immune checkpoint proteins may be associated with disease relapse and progression in acute myeloid leukemia (AML). TOX, a transcription factor in the HMG‐box protein superfamily, was found to be a potential target for immunotherapy not only in solid tumors but also in hematological malignancies. However, little is known about TOX expression and co‐expression with immune checkpoint proteins or the exhausted phenotype in the T cell subsets in AML. Thus, in this study, we analyzed TOX expression and co‐expression with PD‐1, Tim‐3, and CD244 in T cells. Methods TOX expression and co‐expression with PD‐1, Tim‐3, and CD244 in CD3+, CD4+, regulatory T (Treg), and CD8+ T cells were analyzed by multi‐color fluorescent flow cytometry in peripheral blood (PB) and bone marrow (BM) samples from patients with de novo AML and AML in complete remission (CR) and healthy individuals (HIs). Results A significantly increased percentage of TOX+CD3+, CD4+, and CD8+ T cells was found in PB from patients with de novo AML in comparison with HIs. Double‐positive TOX+CD244+, TOX+PD‐1+, and TOX+Tim‐3+ T cells markedly increased in the CD3+, CD4+, and CD8+ T cell populations in de novo AML patients compared with HIs, and similar trends were demonstrated for TOX+Tim‐3+CD3+/CD4+/CD8+ T cells in de novo AML compared with AML‐CR patients. In addition, the number of TOX+, TOX+PD‐1+, and TOX+Tim‐3+Treg cells significantly increased in de novo AML patients compared with HIs, and TOX+PD‐1+Treg cells were higher in de novo AML compared with AML‐CR patients. Moreover, TOX positively correlated with Tim‐3 expression in CD8+ and Treg cells, and a positive correlation between the expression of TOX+ CD4+ and CD244+CD4+ T cells was found. Furthermore, an increased percentage of TOX+Tim‐3+ T cells in BM was also found in de novo AML patients compared with HIs. Conclusions Increased TOX concurrent with PD‐1, Tim‐3, and CD244 in T cells may contribute to T cell exhaustion and impair their function in AML. Such exhausted T cells may be partially revised when AML patients achieve CR after chemotherapy. TOX may be considered a potential target for reversing T cell exhaustion and improving T cell function in AML.

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Characterization of KIR + NKG2A + Eomes− NK‐like CD8+ T cells and their decline with age in healthy individuals

Cited by 9 publications

References 49 publications

Allotransplantation Is Associated With Exacerbation of CD8 T-Cell Senescence: The Particular Place of the Innate CD8 T-Cell Component

Allotransplantation Is Associated With Exacerbation of CD8 T-Cell Senescence: The Particular Place of the Innate CD8 T-Cell Component

Increased IFN‐γ⁺ and TNF‐α⁺ mucosal‐associated invariant T cells in patients with aplastic anemia

Increased TOX expression concurrent with PD‐1, Tim‐3, and CD244 expression in T cells from patients with acute myeloid leukemia

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Characterization of KIR + NKG2A + Eomes− NK‐like CD8+ T cells and their decline with age in healthy individuals

Cited by 9 publications

References 49 publications

Allotransplantation Is Associated With Exacerbation of CD8 T-Cell Senescence: The Particular Place of the Innate CD8 T-Cell Component

Allotransplantation Is Associated With Exacerbation of CD8 T-Cell Senescence: The Particular Place of the Innate CD8 T-Cell Component

Increased IFN‐γ+ and TNF‐α+ mucosal‐associated invariant T cells in patients with aplastic anemia

Increased TOX expression concurrent with PD‐1, Tim‐3, and CD244 expression in T cells from patients with acute myeloid leukemia

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Increased IFN‐γ⁺ and TNF‐α⁺ mucosal‐associated invariant T cells in patients with aplastic anemia