The Critical and Diverse Roles of CD4–CD8– Double Negative T Cells in Nonalcoholic Fatty Liver Disease

Li, Changying; Du, Xinyue; Shen, Zhen; Wei, Yiping; Wang, Yaning; Han, Xiaotong; Jin, Hua; Zhang, Chunpan; Li, Mengyi; Zhang, Zhongtao; Wang, Songlin; Zhang, Dong; Sun, Guan

doi:10.1016/j.jcmgh.2022.02.019

Cited by 10 publications

(8 citation statements)

References 45 publications

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“…Perforin , Granzyme B , and Fasl , which are the main effector molecules of DNT cells [ 13 ], were not altered in IL-33-pre-stimulated DNT cells. The expression of genes encoding potential inhibitory receptors, such as Klra1 , Klra3 , Klrb1b , Klrc1 , and Klrg1 [ 18 ], and activation receptors, such as Klrc2 , Klri2 , Klrk1 , and Cd160 [ 19 ] (Fig. 4E, F ), in two groups were similar.…”

Section: Resultsmentioning

confidence: 99%

IL-33 promotes double negative T cell survival via the NF-κB pathway

et al. 2023

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IL-33, which is a crucial modulator of adaptive immune responses far beyond type 2 response, can enhance the function of several T cell subsets and maintain the immune homeostasis. However, the contribution of IL-33 to double negative T (DNT) cell remains unappreciated. Here, we demonstrated that the IL-33 receptor ST2 was expressed on DNT cells, and that IL-33 stimulation increased DNT cells proliferation and survival in vivo and in vitro. Transcriptome sequencing analysis also demonstrated that IL-33 enhanced the biological function of DNT cells, especially effects on proliferation and survival. IL-33 promoted DNT cells survival by regulating Bcl-2, Bcl-xl and Survivin expression. IL-33-TRAF4/6-NF-κB axis activation promoted the transmission of essential division and survival signals in DNT cells. However, IL-33 failed to enhance the expression of immunoregulatory molecules in DNT cells. DNT cells therapy combined with IL-33 inhibited T cells survival and further ameliorated ConA-induced liver injury, which mainly depended on the proliferative effect of IL-33 on DNT cells in vivo. Finally, we stimulated human DNT cells with IL-33, and similar results were observed. In conclusion, we revealed a cell intrinsic role of IL-33 in the regulation of DNT cells, thereby identifying a previously unappreciated pathway supporting the expansion of DNT cells in the immune environment.

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Section: Resultsmentioning

confidence: 99%

IL-33 promotes double negative T cell survival via the NF-κB pathway

et al. 2023

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“…Perforin, Granzyme B, and Fasl, which are the main effector molecules of DNT cells [13], were not altered in IL-33-prestimulated DNT cells. The expression of genes encoding potential inhibitory receptors, such as Klra1, Klra3, Klrb1b, NKG2A and Klrg1 [17], and activation receptors, such as Klrb1a, Klrc2, Klri2, NKG2D and CD160 [18] (Figure 4G and Figure 4H), in the two groups was similar. These data revealed that IL-33 stimulation has little effect on immunoregulatory molecule expression in DNT cells.…”

Section: Il-33 Stimulation Did Not Enhance the Expression Of Immunore...mentioning

confidence: 85%

IL-33 promotes double negative T cell survival via the NF-κB pathway

Sun

Zhang

Sun

et al. 2022

Preprint

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IL-33, which is a crucial modulator of adaptive immune responses far beyond type 2 response, can enhance the function of several T cell subsets and maintain the immune homeostasis. However, the contribution of IL-33 to double negative T (DNT) cell remains unappreciated. Here, we demonstrated that the IL-33 receptor ST2 was expressed on DNT cells, and that IL-33 stimulation increased DNT cell proliferation and survival in vivo and in vitro. Transcriptome sequencing analysis also demonstrated that IL-33 enhanced the biological function of DNT cells, especially their effects on proliferation and survival. IL-33 promoted DNT cells survival by regulating Bcl-2 and Survivin expression. IL-33-TRAF4/6-NF-κB axis activation promoted the transmission of essential division and survival signals in DNT cells. However, IL-33 failed to enhance the expression of immunoregulatory molecules in DNT cells. DNT cell therapy combined with IL-33 inhibited T cell survival and further ameliorated ConA-induced liver injury, which mainly depended on the proliferative effect of IL-33 on DNT cells in vivo. Finally, we stimulated human DNT cells with IL-33, and similar results were observed. In conclusion, we revealed a cell intrinsic role of IL-33 in the regulation of DNT cells, thereby identifying a previously unappreciated pathway supporting the expansion of DNT cells in the immune environment.

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“…Moreover, the effects of NKT cells on cerebral stroke severity are still remain controversial [43]. Our recent study also demonstrated that, in contrast to TCRαβ + DNT cells, TCRγδ + DNT cells exert proinflammatory effects in the inflammatory tissue of non-alcoholic steatohepatitis [44]. Due to these contradictory characteristics of DNT cell subsets, we excluded TCRγδ+ DNT and NKT cells in this study.…”

Section: Discussionmentioning

confidence: 99%

TCRαβ⁺NK1.1^-CD4^-CD8^- double-negative T cells inhibit central and peripheral inflammation and ameliorate ischemic stroke in mice

Tian¹,

Pan²,

Zhao³

et al. 2023

Theranostics

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Background: Excessive immune activation leads to secondary injury and impedes injured brain recovery after ischemic stroke. However, few effective methods are currently used for equilibrating immune balance. CD3 + NK1.1 -TCRβ + CD4 -CD8 -double-negative T (DNT) cells which do not express NK cell surface markers are unique regulatory cells that maintain homeostasis in several immune-related diseases. However, the therapeutic potential and regulatory mechanism of DNT cells in ischemic stroke are still unknown. Methods: Mouse ischemic stroke is induced by occlusion of the distal branches of the middle cerebral artery (dMCAO). DNT cells were adoptively transferred intravenously into ischemic stroke mice. Neural recovery was evaluated by TTC staining and behavioral analysis. Using immunofluorescence, flow cytometry, and RNA sequencing, the immune regulatory function of DNT cells was investigated at different time points post ischemic stroke. Results: Adoptive transfer of DNT cells significantly reduces infarct volume and improves sensorimotor function after ischemic stroke. DNT cells suppress peripheral Trem1 + myeloid cell differentiation during the acute phase. Furthermore, they infiltrate the ischemic tissue via CCR5 and equilibrate the local immune balance during the subacute phase. During the chronic phase, DNT cells enhance Treg cell recruitment through CCL5, eventually developing an immune homeostatic milieu for neuronal recovery. Conclusions: DNT cell treatment renders the comprehensive anti-inflammatory roles in specific phases of ischemic stroke. Our study suggests that the adoptive transfer of regulatory DNT cells may be a potential cell-based therapy for ischemic stroke.

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The Critical and Diverse Roles of CD4–CD8– Double Negative T Cells in Nonalcoholic Fatty Liver Disease

Cited by 10 publications

References 45 publications

IL-33 promotes double negative T cell survival via the NF-κB pathway

IL-33 promotes double negative T cell survival via the NF-κB pathway

IL-33 promotes double negative T cell survival via the NF-κB pathway

TCRαβ⁺NK1.1^-CD4^-CD8^- double-negative T cells inhibit central and peripheral inflammation and ameliorate ischemic stroke in mice

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The Critical and Diverse Roles of CD4–CD8– Double Negative T Cells in Nonalcoholic Fatty Liver Disease

Cited by 10 publications

References 45 publications

IL-33 promotes double negative T cell survival via the NF-κB pathway

IL-33 promotes double negative T cell survival via the NF-κB pathway

IL-33 promotes double negative T cell survival via the NF-κB pathway

TCRαβ+NK1.1-CD4-CD8- double-negative T cells inhibit central and peripheral inflammation and ameliorate ischemic stroke in mice

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TCRαβ⁺NK1.1^-CD4^-CD8^- double-negative T cells inhibit central and peripheral inflammation and ameliorate ischemic stroke in mice