Increased circulating IL-9-producing CD8+ T cells are associated with eosinophilia and high FeNO in allergic asthmatics

Wang, Wei; Cheng, Zhenshun; Chen, Yifei; Lin, Yani

doi:10.3892/etm.2016.3870

Cited by 9 publications

(7 citation statements)

References 31 publications

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“…As one of the recently described CD8 + T cell subsets, Tc9 cells are generated by differentiating naive CD8 + T cells under Th9-polarizing medium and featured by IL-9 secretion ( 17 , 42 ). Tc9 cells have been detected in atopic dermatitis lesions of mice and humans ( 42 ), in the small intestine ( 43 ), and in the peripheral blood of patients with allergic asthma ( 44 ). Although IL-9–secreting Tc9 cells are less cytolytic in vitro, they produce comparable levels of IFN-γ and granzyme B as Tc1 cells in spleen and tumors after adoptive transfer.…”

Section: Discussionmentioning

confidence: 99%

IL-9/STAT3/fatty acid oxidation–mediated lipid peroxidation contributes to Tc9 cell longevity and enhanced antitumor activity

Xiao¹,

Ma²,

Ye³

et al. 2022

Journal of Clinical Investigation

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CD8 + T cell longevity regulated by metabolic activity plays important roles in cancer immunotherapy. Although in vitro polarized, transferred IL-9-secreting CD8 + Tc9 cells exert greater persistence and antitumor efficacy than Tc1/CTL cells, the underlying mechanism remains unclear. Here, we show that tumor-infiltrating Tc9 cells display significantly lower lipid peroxidation than Tc1 cells in several mouse models, which is strongly correlated with their persistence. Using RNA-sequence and functional validation, we found that Tc9 cells exhibited unique lipid metabolic programs. Tc9 cell-derived IL-9 activated STAT3, upregulated fatty acid oxidation and mitochondrial activity, and rendered Tc9 cells with reduced lipid peroxidation and resistant to tumor or ROS induced ferroptosis in TME. IL-9 signal deficiency, inhibiting STAT3 or fatty acid oxidation increased lipid peroxidation and ferroptosis of Tc9 cells, resulting in impaired longevity and antitumor ability. Similarly, human Tc9 cells also possessed lower lipid peroxidation than Tc1 cells and tumor-infiltrating CD8 + T cells expressed lower IL9 and higher lipid peroxidation-and ferroptosis-related genes than circulating CD8 + T cells in melanoma patients. This study indicates that lipid peroxidation regulates Tc9-cell longevity and antitumor effects via IL-9/STAT3/fatty acid oxidation pathway and regulating T-cell lipid peroxidation can be used to enhance T-cell based immunotherapy in human cancer.

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Section: Discussionmentioning

confidence: 99%

IL-9/STAT3/fatty acid oxidation–mediated lipid peroxidation contributes to Tc9 cell longevity and enhanced antitumor activity

Xiao¹,

Ma²,

Ye³

et al. 2022

Journal of Clinical Investigation

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“…Mainly secreted by Th9 cells, IL-9 could stimulate mast cell accumulation in tissues, promote lymphocytes survival, enhance class switching to IgE in B cells, and alter hematopoietic progenitor cell activity, for its receptor expressed on multiple cell types [49]. Recently, IL-9 was reported to be secreted by Tc cell in many diseases [50, 51]. IL-9 was found to be able to mediate S. japonicum infection induced hepatic damage in our previous study [6].…”

Section: Discussionmentioning

confidence: 99%

Changes of CD103-expressing pulmonary CD4+ and CD8+ T cells in S. japonicum infected C57BL/6 mice

et al. 2019

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BackgroundRecent studies have shown that CD103 is an important marker for tissue-resident memory T cells (TRM) which plays an important role in anti-infection. However, the role of CD103+ TRM was not elucidated in the progress of S. japonicum infection induced disease.Methods6–8 weeks old C57BL/6 mice were infected by S. japonicum. Mice were sacrificed and the lungs were removed 5–6 weeks after infection. Immunofluorescent staining and Q-PCR were performed to identify the expression of CD103 molecule. Single cellular populations were made, percentages of CD103 on both CD4+ and CD8+ T lymphocytes were dynamical observed by flow cytometry (FCM). Moreover, the expression of memory T cells related molecules CD69 and CD62L, T cell function associated molecules CD107a, IFN-γ, IL-4, IL-9, and IL-10 were compared between CD103+ CD4+ and CD8+ T cells by FCM.ResultsCD103+ cells were emerged in the lung of both naive and S. japonicum infected mice. Both the percentage and the absolute numbers of pulmonary CD4+ and CD8+ cells were increased after S. japonicum infection (P < 0.05). The percentage of CD103+ cells in CD8+ T cells decreased significantly at the early stage of S. japonicum infection (P < 0.05). Increased CD69, decreased CD62L and CD107a expressions were detected on both CD4+ and CD8+ CD103+ T cells in the lungs of infected mice (P < 0.05). Compared to CD8+ CD103+ T cells, CD4+ CD103+ T cells from infected mice expressed higher level of CD69 and lower level CD62L molecules (P < 0.05). Moreover, higher percentage of IL-4+, IL-9+ and IL-10+ cells on CD4+ CD103+ pulmonary T cells was found in infected mice (P < 0.05). Significantly increased IL-4 and IL-9, and decreased IFN-γ expressing cells were detected in CD8+CD103+ cells of infected mice (P < 0.05).ConclusionsCD103-expressing pulmonary CD4+ and CD8+ T cells play important roles in mediating S. japonicum infection induced granulomatous inflammation in the lung.

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“…Asthmatic patients with reduced number of IFN-γ + CD8 T cells (Tc1) and high frequency of IL-13 + CD8 T cells (Tc2) was associated with severity of disease [ 20 ]. High frequency of IL-9 + CD8 T cells (Tc9) have been associated with eosinophilia and high fractioned exhaled nitric oxide of allergic asthma [ 21 ]. Thus, it is not surprising that the associations with PKCζ are similar for CD4 and CD8 T cells.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Transient Deficiency of PKC Isozyme Levels in Immature Cord Blood T Cells and Its Connection to Anti-Allergic Cytokine Profiles of the Matured Cells

Perveen

Quach

Stark

et al. 2021

IJMS

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Cord blood T cells (CBTC) from a proportion of newborns express low/deficient levels of some protein kinase C (PKC) isozymes, with low levels of PKCζ correlating with increased risk of developing allergy and associated decrease in interferon-gamma (IFN-γ) producing T cells. Interestingly, these lower levels of PKCζ were increased/normalized by supplementing women during pregnancy with n-3 polyunsaturated fatty acids. However, at present, we have little understanding of the transient nature of the deficiency in the neonate and how PKCζ relates to other PKC isozymes and whether their levels influence maturation into IFN-γ producing T cells. There is also no information on PKCζ isozyme levels in the T cell subpopulations, CD4+ and CD8+ cells. These issues were addressed in the present study using a classical culture model of neonatal T cell maturation, initiated with phytohaemagglutinin (PHA) and recombinant human interleukin-2 (rhIL-2). Of the isozymes evaluated, PKCζ, β2, δ, μ, ε, θ and λ/ι were low in CBTCs. The PKC isozyme deficiencies were also found in the CD4+ and CD8+ T cell subset levels of the PKC isozymes correlated between the two subpopulations. Examination of changes in the PKC isozymes in these deficient cells following addition of maturation signals showed a significant increase in expression within the first few hours for PKCζ, β2 and μ, and 1–2 days for PKCδ, ε, θ and λ/ι. Only CBTC PKCζ isozyme levels correlated with cytokine production, with a positive correlation with IFN-γ, interleukin (IL)-2 and tumour necrosis factor-alpha (TNF), and a negative association with IL-9 and IL-10. The findings reinforce the specificity in using CBTC PKCζ levels as a biomarker for risk of allergy development and identify a period in which this can be potentially ‘corrected’ after birth.

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Increased circulating IL-9-producing CD8+ T cells are associated with eosinophilia and high FeNO in allergic asthmatics

Cited by 9 publications

References 31 publications

IL-9/STAT3/fatty acid oxidation–mediated lipid peroxidation contributes to Tc9 cell longevity and enhanced antitumor activity

IL-9/STAT3/fatty acid oxidation–mediated lipid peroxidation contributes to Tc9 cell longevity and enhanced antitumor activity

Changes of CD103-expressing pulmonary CD4+ and CD8+ T cells in S. japonicum infected C57BL/6 mice

Characterization of the Transient Deficiency of PKC Isozyme Levels in Immature Cord Blood T Cells and Its Connection to Anti-Allergic Cytokine Profiles of the Matured Cells

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