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Loss of the orphan nuclear receptor NR2F6 enhances CD8⁺ T-cell memory via IFN-?.

ABSTRACT: Memory formation is a hallmark of T cell-mediated immunity, but how differentiation into either short-lived effector cells (SLECs, CD127^-KLRG1⁺) or memory precursors cells (MPECs, CD127⁺KLRG1^-) and subsequent regulation of long-term memory is adjusted is incompletely understood. Here, we show that loss of the nuclear orphan receptor NR2F6 in germ-line Nr2f6-deficient mice enhances antigen-specific CD8⁺ memory formation up to 70 days after bacterial infection with Listeria monocytogenes (LmOVA) and boosts inflammatory IFN-?, TNF?, and IL-2 cytokine recall responses. Adoptive transfer experiments using Nr2f6^-/- OT-I T-cells showed that the augmented memory formation is CD8⁺ T-cell intrinsic. Although the relative difference between the Nr2f6^+/+ and Nr2f6^-/- OT-I memory compartment declines over time, Nr2f6-deficient OT-I memory T cells mount significantly enhanced IFN-? responses upon reinfection with increased clonal expansion and improved host antigen-specific CD8⁺ T-cell responses. Following a secondary adoptive transfer into naïve congenic mice, Nr2f6-deficient OT-I memory T cells are superior in clearing LmOVA infection. Finally, we show that the commitment to enhanced memory within Nr2f6-deficient OT-I T cells is established in the early phases of the antibacterial immune response and is IFN-? mediated. IFN-? blocking normalized MPEC formation of Nr2f6-deficient OT-I T cells. Thus, deletion or pharmacological inhibition of NR2F6 in antigen-specific CD8⁺ T cells may have therapeutic potential for enhancing early IFN-? production and consequently the functionality of memory CD8⁺ T cells in vivo.

SUBMITTER: Jakic B

PROVIDER: S-EPMC7884426 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Loss of the orphan nuclear receptor NR2F6 enhances CD8+ T-cell memory via IFN-γ.

Jakic Bojana B Olson William J WJ Siegmund Kerstin K Klepsch Victoria V Kimpel Janine J Labi Verena V Zehn Dietmar D Baier Gottfried G Hermann-Kleiter Natascha N

Cell death & disease 20210215 2

Memory formation is a hallmark of T cell-mediated immunity, but how differentiation into either short-lived effector cells (SLECs, CD127-KLRG1+) or memory precursors cells (MPECs, CD127+KLRG1-) and subsequent regulation of long-term memory is adjusted is incompletely understood. Here, we show that loss of the nuclear orphan receptor NR2F6 in germ-line Nr2f6-deficient mice enhances antigen-specific CD8+ memory formation up to 70 days after ba ...[more]

PMID: 33589606

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Project description:BackgroundIn patients with myelodysplastic syndrome (MDS), bone marrow cells have an increased predisposition to apoptosis, yet MDS cells outcompete normal bone marrow (BM)-- suggesting that factors regulating growth potential may be important in MDS. We previously identified v-Erb A related-2 (EAR-2, NR2F6) as a gene involved in control of growth ability.MethodsBone marrow obtained from C57BL/6 mice was transfected with a retrovirus containing EAR-2-IRES-GFP. Ex vivo transduced cells were flow sorted. In some experiments cells were cultured in vitro, in other experiments cells were injected into lethally irradiated recipients, along with non-transduced bone marrow cells. Short-hairpin RNA silencing EAR-2 was also introduced into bone marrow cells cultured ex vivo.ResultsHere, we show that EAR-2 inhibits maturation of normal BM in vitro and in vivo and that EAR-2 transplant chimeras demonstrate key features of MDS. Competitive repopulation of lethally irradiated murine hosts with EAR-2-transduced BM cells resulted in increased engraftment and increased colony formation in serial replating experiments. Recipients of EAR-2-transduced grafts had hypercellular BM, erythroid dysplasia, abnormal localization of immature precursors and increased blasts; secondary transplantation resulted in acute leukemia. Animals were cytopenic, having reduced numbers of erythrocytes, monocytes and granulocytes. Suspension culture confirmed that EAR-2 inhibits granulocytic and monocytic differentiation, while knockdown induced granulocytic differentiation. We observed a reduction in the number of BFU-E and CFU-GM colonies and the size of erythroid and myeloid colonies. Serial replating of transduced hematopoietic colonies revealed extended replating potential in EAR-2-overexpressing BM, while knockdown reduced re-plating ability. EAR-2 functions by recruitment of histone deacetylases, and inhibition of differentiation in 32D cells is dependent on the DNA binding domain.ConclusionsThis data suggest that NR2F6 inhibits maturation of normal BM in vitro and in vivo and that the NR2F6 transplant chimera system demonstrates key features of MDS, and could provide a mouse model for MDS.

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Loss of the orphan nuclear receptor NR2F6 enhances CD8⁺ T-cell memory via IFN-?.

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Loss of the orphan nuclear receptor NR2F6 enhances CD8<sup>+</sup> T-cell memory via IFN-γ.

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Dataset Information

Loss of the orphan nuclear receptor NR2F6 enhances CD8+ T-cell memory via IFN-?.

Publications

Loss of the orphan nuclear receptor NR2F6 enhances CD8<sup>+</sup> T-cell memory via IFN-γ.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Loss of the orphan nuclear receptor NR2F6 enhances CD8⁺ T-cell memory via IFN-?.