A Novel Human CD34(+) Subset That Constitutively Expresses the High Affinity Interleukin-2 Receptor Traffics to Lymph Nodes and Differentiates into CD56Bright Natural Killer Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 314-314
Author(s):  
Aharon G. Freud ◽  
Brian Becknell ◽  
Sameek Roychowdhury ◽  
Hsiaoyin C. Mao ◽  
Amy K. Ferketich ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
Lymph Nodes ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Constitutive Expression ◽  
High Affinity ◽  
Nk Cell Differentiation

Abstract In adult humans, T cells differentiate in the thymus and B cells develop in the bone marrow, but the site(s) of natural killer (NK) cell differentiation are unclear. Here we describe, for the first time, a unique CD34(+) population found in human lymph nodes (LN) that differentiates into NK cells. CD56bright NK cells represent <10% of NK cells in peripheral blood (PB) yet predominate in LN where they can compete for endogenous T cell-derived IL-2 during immune activation due to their unique expression of functional high affinity (HA) interleukin (IL)-2 receptors (IL-2R). We hypothesized that a subset of CD34(+) hematopoietic precursor cells (HPC) might also express functional HA IL-2R and potentially differentiate into CD56bright NK cells via activation with low dose IL-2. We first identified a novel human CD34dimCD45RA(+) HPC in PB with constitutive expression of the HA IL-2R. When cultured in picomolar concentrations of IL-2 that selectively saturate the HA IL-2R, these cells give rise to CD56bright NK cells, and this effect is blocked when IL-2 cannot bind to its HA receptor. This unique CD34(+) population expresses IL-2Rα, CD2, CD7, c-kit, L-selectin, and NKR-P1A, all of which are also expressed by CD56bright NK cells. Unique among total PB CD34(+) cells, this novel population displays high integrin α4β7 expression. This attribute, in addition to its high L-selectin expression, suggested that these cells may traffic to LN where their progeny, CD56bright NK cells, represent the major NK subset. Indeed we found a distinct CD34dimCD45RA(+)α4β7bright population that resides in the T cell rich regions of human LN, and when stimulated in vitro with 10 pM IL-2, this cell gives rise to CD56bright NK cells. This novel population represents only ~6% of all PB CD34(+) HPC yet is the major if not exclusive CD34(+) subset in LN. While murine studies strongly support the notion that most if not all NK cells require IL-15 for their development, these new human data suggest a model for development of a minor human NK subset, the CD56bright NK cells, whereby CD34dimCD45RA(+)α4β7bright HPC constitutively expressing the HA IL-2R traffic to peripheral LN where endogenous T cell-derived IL-2 can drive CD56bright NK cell differentiation in vivo.

scholarly journals Cytomegalovirus-Driven Adaption of Natural Killer Cells in NKG2Cnull Human Immunodeficiency Virus-Infected Individuals

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 239 ◽  
Author(s):  
Emilie M. Comeau ◽  
Kayla A. Holder ◽  
Neva J. Fudge ◽  
Michael D. Grant
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cell Differentiation ◽  
Hiv Infection ◽  
Nk Cells ◽  
Natural Killer ◽  
Cytokine Production ◽  
Zinc Finger Protein ◽  
Nk Cell ◽  
Immunodeficiency Virus ◽  
Nk Cell Differentiation

Expansion of natural killer (NK) cells expressing NKG2C occurs following human cytomegalovirus (HCMV) infection and is amplified by human immunodeficiency virus (HIV) co-infection. These NKG2C-expressing NK cells demonstrate enhanced CD16-dependent cytokine production and downregulate FcεRIγ and promyelocytic leukemia zinc finger protein (PLZF). Lacking NKG2C diminishes resistance to HIV infection, but whether this affects NK cell acquisition of superior antibody-dependent function is unclear. Therefore, our objective was to investigate whether HCMV-driven NK cell differentiation is impaired in NKG2Cnull HIV-infected individuals. Phenotypic (CD2, CD16, CD57, NKG2A, FcεRIγ, and PLZF expression) and functional (cytokine induction and cytotoxicity) properties were compared between HIV–infected NKG2Cnull and NKG2C-expressing groups. Cytokine production was compared following stimulation through natural cytotoxicity receptors or through CD16. Cytotoxicity was measured by anti-CD16-redirected lysis and by classical antibody-dependent cell-mediated cytotoxicity (ADCC) against anti-class I human leukocyte antigen (HLA) antibody-coated cells. Our data indicate highly similar HCMV-driven NK cell differentiation in HIV infection with or without NKG2C. While the fraction of mature (CD57pos) NK cells expressing CD2 (p = 0.009) or co-expressing CD2 and CD16 (p = 0.03) was significantly higher in NKG2Cnull HIV-infected individuals, there were no significant differences in NKG2A, FcεRIγ, or PLZF expression. The general phenotypic and functional equivalency observed suggests NKG2C-independent routes of HCMV-driven NK cell differentiation, which may involve increased CD2 expression.

scholarly journals Monocytes control natural killer cell differentiation to effector phenotypes

Blood ◽  
2011 ◽  
Vol 117 (17) ◽  
pp. 4511-4518 ◽  
Author(s):  
Katrina Soderquest ◽  
Nick Powell ◽  
Carmelo Luci ◽  
Nico van Rooijen ◽  
Andrés Hidalgo ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
In Vivo Model ◽  
Dependent Manner ◽  
Nk Cell Differentiation

Abstract Natural killer (NK) cells play a major role in immunologic surveillance of cancer. Whether NK-cell subsets have specific roles during antitumor responses and what the signals are that drive their terminal maturation remain unclear. Using an in vivo model of tumor immunity, we show here that CD11bhiCD27low NK cells migrate to the tumor site to reject major histocompatibility complex class I negative tumors, a response that is severely impaired in Txb21−/− mice. The phenotypical analysis of Txb21-deficient mice shows that, in the absence of Txb21, NK-cell differentiation is arrested specifically at the CD11bhiCD27hi stage, resulting in the complete absence of terminally differentiated CD11bhiCD27low NK cells. Adoptive transfer experiments and radiation bone marrow chimera reveal that a Txb21+/+ environment rescues the CD11bhiCD27hi to CD11bhiCD27low transition of Txb21−/− NK cells. Furthermore, in vivo depletion of myeloid cells and in vitro coculture experiments demonstrate that spleen monocytes mediate the terminal differentiation of peripheral NK cells in a Txb21- and IL-15Rα–dependent manner. Together, these data reveal a novel, unrecognized role for Txb21 expression in monocytes in promoting NK-cell development and help appreciate how various NK-cell subsets are generated and participate in antitumor immunity.

scholarly journals Natural killer cell behavior in lymph nodes revealed by static and real-time imaging

2006 ◽  
Vol 203 (3) ◽  
pp. 619-631 ◽  
Author(s):  
Marc Bajénoff ◽  
Béatrice Breart ◽  
Alex Y.C. Huang ◽  
Hai Qi ◽  
Julie Cazareth ◽  
...  
Keyword(s):  
T Cell ◽  
Lymph Nodes ◽  
Nk Cells ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Leishmania Major ◽  
Nk Cell ◽  
Killer Cell

Natural killer (NK) cells promote dendritic cell (DC) maturation and influence T cell differentiation in vitro. To better understand the nature of the putative interactions among these cells in vivo during the early phases of an adaptive immune response, we have used immunohistochemical analysis and dynamic intravital imaging to study NK cell localization and behavior in lymph nodes (LNs) in the steady state and shortly after infection with Leishmania major. In the LNs of naive mice, NK cells reside in the medulla and the paracortex, where they closely associate with DCs. In contrast to T cells, intravital microscopy revealed that NK cells in the superficial regions of LNs were slowly motile and maintained their interactions with DCs over extended times in the presence or absence of immune-activating signals. L. major induced NK cells to secrete interferon-γ and to be recruited to the paracortex, where concomitant CD4 T cell activation occurred. Therefore, NK cells form a reactive but low mobile network in a strategic area of the LN where they can receive inflammatory signals, interact with DCs, and regulate colocalized T cell responses.

scholarly journals Role of interleukin-2 (IL-2), IL-7, and IL-15 in natural killer cell differentiation from cord blood hematopoietic progenitor cells and from gamma c transduced severe combined immunodeficiency X1 bone marrow cells

Blood ◽  
1996 ◽  
Vol 88 (10) ◽  
pp. 3901-3909 ◽  
Author(s):  
M Cavazzana-Calvo ◽  
S Hacein-Bey ◽  
G de Saint Basile ◽  
C De Coene ◽  
F Selz ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cord Blood ◽  
Nk Cells ◽  
Progenitor Cells ◽  
Nk Cell ◽  
Severe Combined Immunodeficiency ◽  
Interleukin 2 ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Nk Cell Differentiation

Natural killer (NK) cells are characterized by their ability to mediate spontaneous cytotoxicity against susceptible tumor cells and infected cells. They differentiate from hematopoietic progenitor cells. Patients with X-linked severe combined immunodeficiency (SCID X1) carry mutations in the gamma c cytokine receptor gene that result in lack of both T and NK cells. To assess the role of interleukin-2 (IL-2), IL-7, and IL-15 cytokines, which share gamma c receptor subunit, in NK cell differentiation, we have studied NK cell differentiation from cord blood CD34 (+) cells in the presence of either stem cell factor (SCF), IL-2, and IL-7 or SCF and IL-15. The former cytokine combination efficiently induced CD34 (+) CD7 (+) cord blood cells to proliferate and mature into NK cells, while the latter was also able to induce NK cell differentiation from more immature CD34 (+) CD7 (-) cord blood cells. NK cells expressed CD56 and efficiently killed K562 target cells. These results show that IL-15 could play an important role in the maturation of NK cell from cord blood progenitors. Following retroviral-mediated gene transfer of gamma c into SCID X1 bone marrow progenitors, it was possible to reproduce a similar pattern of NK cell differentiation in two SCID-X1 patients with SCF + IL-2 + IL-7 and more efficiently in one of them with SCF + IL-15. These results strongly suggest that the gamma c chain transduces major signal(s) involved in NK cell differentiation from hematopoietic progenitor cells and that IL-15 interaction with gamma c is involved in this process at an earlier step than IL-2/IL-7 interactions of gamma c are. It also shows that gene transfer into hematopoietic progenitor cells could potentially restore NK cell differentiation in SCID X1 patients.

scholarly journals Natural Killer Cell–Mediated Eradication of Neuroblastoma Metastases to Bone Marrow by Targeted Interleukin-2 Therapy

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1706-1715 ◽  
Author(s):  
Holger N. Lode ◽  
Rong Xiang ◽  
Torsten Dreier ◽  
Nissi M. Varki ◽  
Stephen D. Gillies ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Fusion Protein ◽  
Nk Cells ◽  
Natural Killer ◽  
Therapeutic Effect ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Interleukin 2

Targeted interleukin-2 (IL-2) therapy with a genetically engineered antidisialoganglioside GD2 antibody–IL-2 fusion protein induced a cell-mediated antitumor response that effectively eradicated established bone marrow and liver metastases in a syngeneic model of neuroblastoma. The mechanism involved is exclusively natural killer (NK) cell–dependent, because NK-cell deficiency abrogated the antitumor effect. In contrast, the fusion protein remained completely effective in the T-cell–deficient mice or immunocompetent mice depleted of CD8+ T cells in vivo. A strong stimulation of NK-cell activity was also shown in vitro. Immunohistology of the leukocytic infiltrate of livers from treated mice revealed a strong staining for NK cells but not for CD8+ T cells. The therapeutic effect of the fusion protein was increased when combined with NK-cell–stimulating agents, such as poly I:C or recombinant mouse interferon-γ. In conclusion, these data show that targeted delivery of cytokines to the tumor microenvironment offers a new strategy to elicit an effective cellular immune response mediated by NK cells against metastatic neuroblastoma. This therapeutic effect may have general clinical implications for the treatment of patients with minimal residual disease who suffer from T-cell suppression after high-dose chemotherapy but are not deficient in NK cells.

scholarly journals Definition of a natural killer NKR-P1A+/CD56-/CD16- functionally immature human NK cell subset that differentiates in vitro in the presence of interleukin 12.

1996 ◽  
Vol 184 (5) ◽  
pp. 1845-1856 ◽  
Author(s):  
I M Bennett ◽  
O Zatsepina ◽  
L Zamai ◽  
L Azzoni ◽  
T Mikheeva ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Cell Subset ◽  
Interleukin 12 ◽  
Ifn Gamma ◽  
Differentiation Antigens ◽  
Nk Cell Differentiation

Human natural killer (NK) cell differentiation from immature lineage negative (Lin-) umbilical cord blood cells was examined in vitro. Cells expressing differentiation antigens of mature NK cells (CD56, CD16, CD2, CD8, NKR-P1A) were generated from Lin- cells cultured with interleukin (IL)-2 and a murine bone marrow stromal cell line expressing the human membrane-bound form of stem cell factor. Two subsets of NK cells were identified in these cultures: one expressed both NKR-P1A and CD56 and, in variable proportions, all other NK cell differentiation antigens; the second subset expressed only NKR-P1A and, unlike the former, was not cytotoxic. Neither subset expressed interferon (IFN)-gamma mRNA even after stimulation with phorbol di-ester and Ca2+ ionophore, but both expressed tumor necrosis factor alpha mRNA and the cytotoxic granule-associated proteins TIA-1, perforin, and serine esterase-1. After 10-d culture with IL-2, IL-12, and irradiated B lymphoblastoid cells, approximately 45% of the NKR-P1A+/ CD56- cells became CD56+, and the same cultures contained cells capable of cytotoxicity and of IFN-gamma production. These results indicate that NKR-P1A expression in the absence of other NK cell markers defines an intermediate, functionally immature stage of NK cell differentiation, and that effector functions develop in these cells, concomitantly with CD56 expression, in the presence of IL-12. These cells likely represent the counterpart of a CD3-/NKR-P1A+/ CD56-/CD16- cell subset that, as shown here, is present both in adult and neonatal circulating lymphocytes.

scholarly journals Natural Killer Cell–Mediated Eradication of Neuroblastoma Metastases to Bone Marrow by Targeted Interleukin-2 Therapy

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1706-1715 ◽  
Author(s):  
Holger N. Lode ◽  
Rong Xiang ◽  
Torsten Dreier ◽  
Nissi M. Varki ◽  
Stephen D. Gillies ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Fusion Protein ◽  
Nk Cells ◽  
Natural Killer ◽  
Therapeutic Effect ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Interleukin 2

Abstract Targeted interleukin-2 (IL-2) therapy with a genetically engineered antidisialoganglioside GD2 antibody–IL-2 fusion protein induced a cell-mediated antitumor response that effectively eradicated established bone marrow and liver metastases in a syngeneic model of neuroblastoma. The mechanism involved is exclusively natural killer (NK) cell–dependent, because NK-cell deficiency abrogated the antitumor effect. In contrast, the fusion protein remained completely effective in the T-cell–deficient mice or immunocompetent mice depleted of CD8+ T cells in vivo. A strong stimulation of NK-cell activity was also shown in vitro. Immunohistology of the leukocytic infiltrate of livers from treated mice revealed a strong staining for NK cells but not for CD8+ T cells. The therapeutic effect of the fusion protein was increased when combined with NK-cell–stimulating agents, such as poly I:C or recombinant mouse interferon-γ. In conclusion, these data show that targeted delivery of cytokines to the tumor microenvironment offers a new strategy to elicit an effective cellular immune response mediated by NK cells against metastatic neuroblastoma. This therapeutic effect may have general clinical implications for the treatment of patients with minimal residual disease who suffer from T-cell suppression after high-dose chemotherapy but are not deficient in NK cells.

scholarly journals Human fetal liver-derived CD7+CD2lowCD3-CD56- clones that express CD3 gamma, delta, and epsilon and proliferate in response to interleukin-2 (IL-2), IL-3, IL-4, or IL-7: implications for the relationship between T and natural killer cells

Blood ◽  
1992 ◽  
Vol 80 (5) ◽  
pp. 1270-1278 ◽  
Author(s):  
T Hori ◽  
JH Phillips ◽  
B Duncan ◽  
LL Lanier ◽  
H Spits
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Fetal Liver ◽  
Interleukin 2 ◽  
Gamma Delta ◽  
Low Levels ◽  
The Relationship ◽  
Adult Bone

Cells from fetal liver or fetal and adult bone marrow that are membrane (m)CD3 negative and have not rearranged TCR genes but express CD3 proteins in their cytoplasm are considered to be committed T-cell progenitors. Recent findings question whether CD3 is T-cell specific because fetal natural killer (NK) cells have been shown to express cCD3 delta and epsilon proteins. To further examine the relationship between T and NK cells, we generated mCD3-cCD3+ clones from fetal liver. Two stable clones, FL412 and FL508, isolated from different donors, were selected on the basis of absence of the NK cell marker CD56. These clones shared a common phenotype of CD7+CD2lowCD3-CD4-CD8-CD5-CD6- CD11b+CD16-CD56 -. Like fetal NK clones, these clones expressed cytoplasmic CD3 delta and epsilon transcripts and proteins. However, the clones exhibited no or very low levels of cytotoxic activity against K562, JY, or Daudi, which were lysed efficiently by fetal NK clones. TCR beta, gamma, and delta genes in these clones were in germline configuration. Furthermore, both FL412 and FL508 responded not only to interleukin-2 (IL-2), IL-4, or IL-7, but also to IL-3 with proliferation. These results suggest that FL412 and FL508 retained some characteristics of a putative T or NK precursor in the fetal liver and may be useful for analyses of this poorly defined cell type.

scholarly journals Human fetal liver-derived CD7+CD2lowCD3-CD56- clones that express CD3 gamma, delta, and epsilon and proliferate in response to interleukin-2 (IL-2), IL-3, IL-4, or IL-7: implications for the relationship between T and natural killer cells

Blood ◽  
1992 ◽  
Vol 80 (5) ◽  
pp. 1270-1278 ◽  
Author(s):  
T Hori ◽  
JH Phillips ◽  
B Duncan ◽  
LL Lanier ◽  
H Spits
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Fetal Liver ◽  
Interleukin 2 ◽  
Gamma Delta ◽  
Low Levels ◽  
The Relationship ◽  
Adult Bone

Abstract Cells from fetal liver or fetal and adult bone marrow that are membrane (m)CD3 negative and have not rearranged TCR genes but express CD3 proteins in their cytoplasm are considered to be committed T-cell progenitors. Recent findings question whether CD3 is T-cell specific because fetal natural killer (NK) cells have been shown to express cCD3 delta and epsilon proteins. To further examine the relationship between T and NK cells, we generated mCD3-cCD3+ clones from fetal liver. Two stable clones, FL412 and FL508, isolated from different donors, were selected on the basis of absence of the NK cell marker CD56. These clones shared a common phenotype of CD7+CD2lowCD3-CD4-CD8-CD5-CD6- CD11b+CD16-CD56 -. Like fetal NK clones, these clones expressed cytoplasmic CD3 delta and epsilon transcripts and proteins. However, the clones exhibited no or very low levels of cytotoxic activity against K562, JY, or Daudi, which were lysed efficiently by fetal NK clones. TCR beta, gamma, and delta genes in these clones were in germline configuration. Furthermore, both FL412 and FL508 responded not only to interleukin-2 (IL-2), IL-4, or IL-7, but also to IL-3 with proliferation. These results suggest that FL412 and FL508 retained some characteristics of a putative T or NK precursor in the fetal liver and may be useful for analyses of this poorly defined cell type.

scholarly journals The transcription factor Bcl11b promotes both canonical and adaptive NK cell differentiation

2021 ◽  
Vol 6 (57) ◽  
pp. eabc9801
Author(s):  
Tim D. Holmes ◽  
Ram Vinay Pandey ◽  
Eric Y. Helm ◽  
Heinrich Schlums ◽  
Hongya Han ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
T Cell ◽  
Nk Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
Murine Cytomegalovirus ◽  
Nk Cell Differentiation ◽  
And Function

Epigenetic landscapes can provide insight into regulation of gene expression and cellular diversity. Here, we examined the transcriptional and epigenetic profiles of seven human blood natural killer (NK) cell populations, including adaptive NK cells. The BCL11B gene, encoding a transcription factor (TF) essential for T cell development and function, was the most extensively regulated, with expression increasing throughout NK cell differentiation. Several Bcl11b-regulated genes associated with T cell signaling were specifically expressed in adaptive NK cell subsets. Regulatory networks revealed reciprocal regulation at distinct stages of NK cell differentiation, with Bcl11b repressing RUNX2 and ZBTB16 in canonical and adaptive NK cells, respectively. A critical role for Bcl11b in driving NK cell differentiation was corroborated in BCL11B-mutated patients and by ectopic Bcl11b expression. Moreover, Bcl11b was required for adaptive NK cell responses in a murine cytomegalovirus model, supporting expansion of these cells. Together, we define the TF regulatory circuitry of human NK cells and uncover a critical role for Bcl11b in promoting NK cell differentiation and function.

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