T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow

Daussy, Christophe; Faure, Fabrice; Mayol, Katia; Viel, Sébastien; Gasteiger, Georg; Charrier, Emily; Bienvenu, Jacques; Henry, Thomas; Debien, Emilie; Hasan, Uzma; Marvel, Jacqueline; Yoh, Keigyou; Takahashi, Satoru; Prinz, Immo; Bernard, Simon; Buffat, Laurent; Walzer, Thierry

doi:10.1084/jem.20131560

Cited by 485 publications

(653 citation statements)

References 73 publications

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“…Finally, this study also confirmed that the liver-resident CD49a + DX5 − subset of NK cells are responsible for hapten-induced NK cell memory (Peng et al 2013). Follow-up reports showed that development of these NK cells is dependent on T-bet, but not Eomes, in contrast to conventional NK cells developing in the bone marrow (Daussy et al 2014). In human livers, Marquardt et al identified a similar T-bet + Eomes − CD49a + NK cell subset, with similar functional properties (high cytokine output, low degranulation potential) (Marquardt et al 2015).…”

Section: Insights Into the Mechanism Of Nk Cell Memory In Contact Hypsupporting

confidence: 79%

Sweet Is the Memory of Past Troubles: NK Cells Remember

Hendricks

Min‐Oo

Lanier

2015

Natural Killer Cells

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Natural killer (NK) cells are important in host defense against tumors and microbial pathogens. Recent studies indicate that NK cells share many features with the adaptive immune system, and like B cells and T cells, NK cells can acquire immunological memory. Here, we review evidence for NK cell memory and the molecules involved in the generation and maintenance of these self-renewing NK cells that provide enhanced protection of the host.

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Section: Insights Into the Mechanism Of Nk Cell Memory In Contact Hypsupporting

confidence: 79%

Sweet Is the Memory of Past Troubles: NK Cells Remember

Hendricks

Min‐Oo

Lanier

2015

Natural Killer Cells

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“…Diversity in the NK-cell lineage generally refers to the presence of phenotypically and functionally distinct subsets of peripheral NK cells. The fact that tissue-specific NK-cell populations with unique transcription factor requirements for their development have been described in liver [21][22][23], thymus [37], skin and uterus [23], suggests that part of the observed diversity might be due to the presence of separate NK-cell lineages. However, more recent data suggest that these tissue-resident NK cells might be related to non-NK ILC1 sharing with NK cells some phenotypic features (NKp46 and NK1.1 expression) while lacking others (expression of NK-cell markers like Ly49 molecules and DX5) [24,25] Ample evidence suggests that NK cells are important for the immune response to B16 melanoma [15,[39][40][41].…”

Section: Discussionmentioning

confidence: 99%

“…Further analyses are needed to clarify the relationships among these ILC1 subsets and whether or not other ILC1 subsets exist. Tissue-resident NK cells appear to have functional capacities that differ from NK cells when assayed in vitro [21][22][23]37]. Whether tissue-resident NK cells possess unique functionally relevant roles in immune responses in vivo is not fully understood.…”

Section: Discussionmentioning

confidence: 99%

“…Ncr1 encodes the cell surface glycoprotein NKp46 that is specifically expressed by NK cells [20], including classical and tissueresident NK cells [21][22][23], a recently identified novel lineage of non-NK ILC1 in the gut [24,25], and a subset of group 3 ILCs [26][27][28]. To further study gene function in NKp46 + cells, we generated Ncr1 greenCre transgenic mice expressing an EGFPcre fusion under the control of the proximal 623bp-fragment of the murine (C57BL/6) Ncr1 promoter (Fig.…”

Section: Generation Of Ncr1 Greencre Micementioning

confidence: 99%

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Conditional ablation of NKp46⁺ cells using a novel Ncr1^greenCre mouse strain: NK cells are essential for protection against pulmonary B16 metastases

et al. 2014

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To study gene functions specifically in NKp46 + cells we developed novel Cre mice allowing for conditional gene targeting in cells expressing Ncr1 (encoding NKp46). We generated transgenic Ncr1 greenCre mice carrying an EGFPcre fusion under the control of a proximal Ncr1 promoter that faithfully directed EGFPcre expression to NKp46 + cells from lymphoid and nonlymphoid tissues. This approach allowed for direct detection of Cre-expressing NKp46 + cells via their GFP signature by flow cytometry and histology. Cre was functional as evidenced by the NKp46 + cell-specific expression of RFP in Ncr1 greenCre RosadtRFP reporter mice. We generated Ncr1 greenCre Il2rg fl/fl mice that lack NKp46 + cells in an otherwise intact hematopoietic environment. Il2rg encodes the common gamma chain (γ c ), which is an essential receptor subunit for cytokines (IL-2, -4, -7, -9, -15, and -21) that stimulate lymphocyte development and function. In Ncr1 greenCre Il2rg fl/fl mice, NK cells are severely reduced and the few remaining NKp46 + cells escaping γc deletion failed to express GFP. Using this new NK-cell-deficient model, we demonstrate that the homeostasis of NKp46 + cells from all tissues (including the recently described intraepithelial ILC1 subset) requires Il2rg. Eur. J. Immunol. 2014. 44: 3380-3391 Innate immunity 3381 in vivo and their capacity to promptly kill target cells (including tumors and infected cells) without prior sensitization [1][2][3]. NK cells have been shown to participate in immune responses to various microbial pathogens, including viruses, bacteria, and parasites (reviewed in [4]) through secretion of type 1 cytokines that recruit and activate hematopoietic effector cells. In the mouse, NK cells can be identified as CD3-NKp46 + cells that coexpress NK1.1 on appropriate genetic backgrounds (including C57BL/6). NK cells do not represent a homogeneous cell population but can be phenotypically separated into several subpopulations. Commonly used cell surface markers include CD27 and CD11b that divide NK-cell populations into CD27 + CD11b − NK cells (representing the least differentiated cells) that give rise to CD27 − CD11b + NK cells via CD27 + CD11b + NK-cell intermediates [5,6]. CD11b + NK cells can be further subdivided on the basis of KLRG1 expression with KLRG1 + marking terminally differentiated NK cells [7]. NK cells have been detected in lymphoid tissues, including bone marrow (BM), spleen, lymph nodes (LNs), Peyer's patches, and thymus, but also in nonlymphoid tissues, including liver, lungs, uterus, pancreas, skin, and intestine (reviewed in [8]).Many studies aiming at deciphering gene functions for NK cells make use of germ-line gene targeted mice where all cells lack the gene in question. Given that the activity and differentiation of NK cells is intimately regulated by other immune cells (reviewed in [9,10]), the consequences of gene deletions that intrinsically affect NK cells may be difficult to distinguish from indirect effects that occur in non-NK cells. Furthermore, studying the role of N...

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“…In the immune system, Eomes functions redundantly with T-bet in the induction of IFN-g production and cytotoxicity in CD8 + T lymphocytes (14). Although most of the described immune roles for Eomes in vivo are redundant with T-bet, unique functions of Eomes have also been described, notably in the maintenance of CD8 + T cells after activation (15,16) and in the development of classical NK cells (17,18). In contrast, the role of Eomes in CD4 + T cell polarization is less defined.…”

Section: T He Cd4 + T Cells Coordinate Different Types Of Immunementioning

confidence: 99%

Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

Lupar¹,

Brack

Garnier

et al. 2015

The Journal of Immunology

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CD4+ T cells polarize into effector Th subsets characterized by signature transcription factors and cytokines. Although T-bet drives Th1 responses and represses the alternative Th2, Th17, and Foxp3+ regulatory T cell fates, the role of the T-bet–related transcription factor eomesodermin (Eomes) in CD4+ T cells is less well understood. In this study, we analyze the expression and effects of Eomes in mouse CD4+ T lymphocytes. We find that Eomes is readily expressed in activated CD4+ Th1 T cells in vivo. Eomes+ CD4+ T cells accumulated in old mice, under lymphopenic conditions in a T cell transfer model of colitis, and upon oral Ag administration. However, despite its expression, genetic deletion of Eomes in CD4+ T cells did not impact on IFN-γ production nor increase Th2 or Th17 responses. In contrast, Eomes deficiency favored the accumulation of Foxp3+ cells in old mice, after in vivo differentiation of Eomes-deficient naive CD4+ T cells, and in response to oral Ag in a cell-intrinsic way. Enforced Eomes expression during in vitro regulatory T cell induction also reduced Foxp3 transcription. Likewise, bystander Eomes-deficient CD4+ T cells were more efficient at protecting from experimental autoimmune encephalitis compared with wild-type CD4+ T cells. This enhanced capacity of Eomes-deficient CD4+ T cells to inhibit EAE in trans was associated with an enhanced frequency of Foxp3+ cells. Our data identify a novel role for Eomes in CD4+ T cells and indicate that Eomes expression may act by limiting Foxp3 induction, which may contribute to the association of EOMES to susceptibility to multiple sclerosis.

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T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow

Abstract: Mutually exclusive expression of T-bet and Eomes drives the development of distinct NK cell lineages with complementary functions.

Cited by 485 publications

References 73 publications

Sweet Is the Memory of Past Troubles: NK Cells Remember

Sweet Is the Memory of Past Troubles: NK Cells Remember

Conditional ablation of NKp46⁺ cells using a novel Ncr1^greenCre mouse strain: NK cells are essential for protection against pulmonary B16 metastases

Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

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T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow

Abstract: Mutually exclusive expression of T-bet and Eomes drives the development of distinct NK cell lineages with complementary functions.

Cited by 485 publications

References 73 publications

Sweet Is the Memory of Past Troubles: NK Cells Remember

Sweet Is the Memory of Past Troubles: NK Cells Remember

Conditional ablation of NKp46+ cells using a novel Ncr1greenCre mouse strain: NK cells are essential for protection against pulmonary B16 metastases

Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

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Conditional ablation of NKp46⁺ cells using a novel Ncr1^greenCre mouse strain: NK cells are essential for protection against pulmonary B16 metastases