Cutting Edge: Thymic NK Cells Develop Independently from T Cell Precursors

Ribeiro, Vera S. G.; Hasan, Milena; Wilson, Anne; Boucontet, Laurent; Pereira, Pablo; Lesjean-Pottier, Sarah; Satoh-Takayama, Naoko; Santo, James P. Di; Vosshenrich, Christian A. J.

doi:10.4049/jimmunol.1002273

Cited by 47 publications

(42 citation statements)

References 27 publications

(40 reference statements)

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“…Furthermore, our choice to use Rag1 Ϫ/Ϫ mice was further supported by a recent publication indicating that thymic NK cells are not derived from thymocytes having undergone antigen receptor rearrangement. 25 While earlier in vitro studies showed that NK1.1 ϩ cells are generated from CD117 ϩ cells within the DN1 thymic population, 17 our studies indicate that in Rag1 Ϫ/Ϫ mice, there is a DN1 CD122 ϩ NK1.1 ϩ population that may have skewed our results if not sorted out. Future experiments to enrich for the CD117 ϩ population may be informative but additional markers will still be needed to markedly increase precursor frequency.…”

Section: Discussionmentioning

confidence: 65%

“…16,17 Recent in vivo experiments further showed that thymic NK cells do not express Rag2 and do not rearrange TCR␥ locus, suggesting that thymic NK cells are not derived from a committed T cell progenitor. 25 In either case, whether these NK1.1 ϩ cells were functional is unknown. Therefore, prior studies provide a framework for considering NK cell differentiation, but further analysis is required to understand the acquisition of markers during development and the relationship of DN1 cells to thymic and conventional NK cells.…”

Section: Introductionmentioning

confidence: 99%

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Development of thymic NK cells from double negative 1 thymocyte precursors

Vargas¹,

Poursine-Laurent

Yang³

et al. 2011

Blood

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IntroductionNK cells are critical innate immune components that do not require prior sensitization to be activated on exposure to tumor or infected cells. 1 On activation, NK cells lyse target cells through degranulation and also produce cytokines such as IFN␥ and TNF␣. 2 While there has been much progress in defining the specificity and function of NK cells, their differentiation process has not been fully elucidated.NK cells are generally thought to be bone marrow (BM)-derived, and differentiate through the sequential acquisition of markers and functional receptors. 3,4 Unlike other lymphocytes, NK cells do not require somatic gene rearrangements for expression of their receptors, and can be found normally in mice defective in antigen receptor gene rearrangement, such as Rag1 Ϫ/Ϫ mice. Current models suggest that NK cell development can be divided into several major steps. 5-7 First, hematopoietic stem cells (HSCs) commit to the NK lineage, becoming natural killer cell precursors (NKPs). Second, the NKPs acquire receptors and molecules involved in target detection, making them immature NK cells (iNKs). Finally, the iNKs terminally differentiate into mature NK cells (mNK) that have appropriate effector functions. Thus, NK cells undergo several developmental steps to become phenotypically and functionally mature. 3,4 In greater detail, the earliest step of murine NK cell differentiation involves the commitment of HSCs to the lymphoid lineage and become early lymphoid progenitors (ELP) (Lin Ϫ cKit high Sca1 ϩ Flt3 ϩ ). 5 Further differentiation generates common lymphoid progenitors (CLP; Lin Ϫ cKit low Sca1 low IL7R␣ ϩ ). 6 The acquisition of CD122 (IL2/IL15R␤) defines the transition from a CLP to a committed NKP. 7 (Mac1) and CD43 and acquire the capacity to kill targets and produce IFN␥. However, it is important to note that these putative developmental stages are based on correlating marker expression in vivo and developmental progression has not been directly observed.While conventional splenic NK cells appear to differentiate in this manner within the BM, CLPs also have the ability to become bipotential T/NK progenitors (T/NKP) and are found in various fetal organs. 9-14 The T/NKP found in fetal thymus can generate either TCR␣␤ T cells or NK cells when transferred into a thymic environment. 15 In addition, a small thymic DN1 (CD4 Ϫ CD8 Ϫ CD44 ϩ CD25 Ϫ , double negative 1) population in adult mice also harbors T/NK potential, 16-18 although these cells were not further characterized. Later studies described an unusual, phenotypically distinct thymic NK cell. 19 These cells were CD127 ϩ CD69 high Ly49 low CD11b low , failed to lyse target cells as well as their splenic counterparts, yet were more efficient at producing cytokines. These cells are absent in athymic nude mice, indicating that a functional thymus is required for their development. However, their relationship to previously described T/NKP cells has not been elucidated. Furthermore, it is not known if their progenitors seed the thymus as cells alrea...

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Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Development of thymic NK cells from double negative 1 thymocyte precursors

Vargas¹,

Poursine-Laurent

Yang³

et al. 2011

Blood

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“…It is known that Notch signaling is essential for T cell commitment in ETPs (32,48). In contrast, Notch signaling is dispensable for thymic NK cell differentiation in mice (49,50 (32,48). Conversely, Notch2 can promote early T cell commitment of Notch1-deficient HSCs in coculture with OP9-DL1 stroma cells and possibly in vivo in the spleen after BM transplantation (32).…”

Section: Discussionmentioning

confidence: 99%

Fate Decision Between Group 3 Innate Lymphoid and Conventional NK Cell Lineages by Notch Signaling in Human Circulating Hematopoietic Progenitors

Kyoizumi

Kubo

Kajimura

et al. 2017

The Journal of Immunology

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The role of Notch signaling in human innate lymphoid cell (ILC) differentiation is unclear, although IL-7 and IL-15 promote differentiation of natural cytotoxicity receptor (NCR) NKp44+ group 3 ILCs (NCR+ILC3s) and conventional NK (cNK) cells from CD34+ hematopoietic progenitor cells (HPCs) ex vivo. In this study, we analyzed the functions of Notch in the differentiation of NCR+ILC3s and cNK cells from human HPC subpopulations circulating in peripheral blood by limiting dilution and clonal assays using high-throughput flow cytometry. We demonstrated that Notch signaling in combination with IL-7 induced NCR+ILC3 differentiation, but conversely suppressed IL-15–dependent cNK cell generation in CD45RA+Flt-3−c-Kitlow, a novel innate lymphocyte-committed HPC subpopulation. In contrast, Notch signaling induced CD45RA−Flt-3+c-Kithigh multipotent HPCs to generate CD34+CD7+CD62Lhigh, the earliest thymic progenitor–like cells, which preserved high cNK/T cell potential, but lost NCR+ILC3 potential. These findings implicate the countervailing functions of Notch signaling in the fate decision between NCR+ILC3 and cNK cell lineages at different maturational stages of human HPCs. Inhibition of Notch functions by Abs specific for either the Notch1 or Notch2 negative regulatory region suggested that both Notch1 and Notch2 signals were involved in the fate decision of innate lymphocyte-committed HPCs and in the generation of earliest thymic progenitor–like cells from multipotent HPCs. Furthermore, the synergistic interaction between Notch and IL-7 in NCR+ILC3 commitment was primarily explicable by the induction of IL-7 receptor expression in the innate lymphocyte–committed HPCs by Notch stimulation, suggesting the pivotal role of Notch in the transcriptional control required for human NCR+ILC3 commitment.

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“…Although Id2 is essential for optimal development of NK cells, this molecule plays an important role at a later developmental stage in the transition of pre-NK to immature NK cells [7,21,59]. Of note, the development of mouse thymic NK cells is dependent on IL-15, IL-7, and Gata-3 [60]. In mice, there is a population of thymic NK cells which are identical to human CD56 hi CD16 dim/À NK cells and express CD127, high levels of Table 1 Characteristics of CD markers, localization and signature cytokine of ILC subsets.…”

Section: Ilc Developmentmentioning

confidence: 98%