scholarly journals Interleukin-2 from Adaptive T Cells Enhances Natural Killer Cell Activity against Human Cytomegalovirus-Infected Macrophages

2015 ◽  
Vol 89 (12) ◽  
pp. 6435-6441 ◽  
Author(s):  
Zeguang Wu ◽  
Giada Frascaroli ◽  
Carina Bayer ◽  
Tatjana Schmal ◽  
Thomas Mertens
Keyword(s):  
Innate Immunity ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Adaptive Immunity ◽  
Human Cytomegalovirus ◽  
Latent Infection ◽  
Immune Surveillance ◽  
Interleukin 2

ABSTRACTControl of human cytomegalovirus (HCMV) requires a continuous immune surveillance, thus HCMV is the most important viral pathogen in severely immunocompromised individuals. Both innate and adaptive immunity contribute to the control of HCMV. Here, we report that peripheral blood natural killer cells (PBNKs) from HCMV-seropositive donors showed an enhanced activity toward HCMV-infected autologous macrophages. However, this enhanced response was abolished when purified NK cells were applied as effectors. We demonstrate that this enhanced PBNK activity was dependent on the interleukin-2 (IL-2) secretion of CD4+T cells when reexposed to the virus. Purified T cells enhanced the activity of purified NK cells in response to HCMV-infected macrophages. This effect could be suppressed by IL-2 blocking. Our findings not only extend the knowledge on the immune surveillance in HCMV—namely, that NK cell-mediated innate immunity can be enhanced by a preexisting T cell antiviral immunity—but also indicate a potential clinical implication for patients at risk for severe HCMV manifestations due to immunosuppressive drugs, which mainly suppress IL-2 production and T cell responsiveness.IMPORTANCEHuman cytomegalovirus (HCMV) is never cleared by the host after primary infection but instead establishes a lifelong latent infection with possible reactivations when the host′s immunity becomes suppressed. Both innate immunity and adaptive immunity are important for the control of viral infections. Natural killer (NK) cells are main innate effectors providing a rapid response to virus-infected cells. Virus-specific T cells are the main adaptive effectors that are critical for the control of the latent infection and limitation of reinfection. In this study, we found that IL-2 secreted by adaptive CD4+T cells after reexposure to HCMV enhances the activity of NK cells in response to HCMV-infected target cells. This is the first direct evidence that the adaptive T cells can help NK cells to act against HCMV infection.

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 Selective generation of erythroid burst-promoting activity by recombinant interleukin 2-stimulated human T lymphocytes and natural killer cells

Blood ◽  
1988 ◽  
Vol 71 (4) ◽  
pp. 907-914
Author(s):  
S Skettino ◽  
J Phillips ◽  
L Lanier ◽  
A Nagler ◽  
P Greenberg
Keyword(s):  
T Cells ◽  
Growth Factors ◽  
T Cell ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Natural Killer ◽  
Inhibitory Activity ◽  
Interleukin 2 ◽  
Gm Csf ◽  
Recombinant Interleukin 2

Because T lymphocytes and natural killer (NK) cells produce a variety of growth factors and interleukin 2 (IL2) modulates the activity of both, we assessed the ability of IL2 to stimulate human T cells and NK cells to produce hematopoietic growth factors detectable in clonogenic marrow culture. Human recombinant interleukin 2 (rIL2) added directly to cultures of human bone marrow that had been depleted of monocytes or depleted of both monocytes and T cells caused no significant alteration of myeloid (CFU-GM) or erythroid colony formation. Conditioned media harvested from rIL2-stimulated (greater than 100 U/mL) peripheral blood mononuclear cells, T cells, Leu-2 cells, and Leu-3 cells all had erythroid burst-promoting activity (BPA) but lacked myeloid colony- stimulating factor (GM-CSF) or CFU-GM-inhibitory activity. These T cells were IL2 receptor-negative, and the addition of anti-IL2 receptor monoclonal antibody (anti-Tac) to T cell cultures did not abrogate this IL2-stimulated BPA production. In addition, Percoll gradient-enriched, large granular lymphocytes (LGL) were separated by fluorescence- activated cell sorting into Leu-11+ (NK) cells and Leu-11- (low-density Leu-4+ T) cell fractions. rIL2 stimulated LGL, Leu-11+ and Leu-11- cells to produce BPA but not detectable GM-CSF or CFU-GM-inhibitory activity. Leu-11+ (NK) cells were Tac-negative from days 0 through 14 of culture. We conclude that rIL2 at high concentrations stimulated T cells, Leu-2 and Leu-3 cell subsets, LGL, and NK cells to produce BPA but not GM-CSF and that this stimulation may be mediated by an IL2 receptor distinct from Tac or by an epitope of the IL2 receptor not recognized by the anti-Tac antibody.

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 Selective generation of erythroid burst-promoting activity by recombinant interleukin 2-stimulated human T lymphocytes and natural killer cells

Blood ◽  
1988 ◽  
Vol 71 (4) ◽  
pp. 907-914 ◽  
Author(s):  
S Skettino ◽  
J Phillips ◽  
L Lanier ◽  
A Nagler ◽  
P Greenberg
Keyword(s):  
T Cells ◽  
Growth Factors ◽  
T Cell ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Natural Killer ◽  
Inhibitory Activity ◽  
Interleukin 2 ◽  
Gm Csf ◽  
Recombinant Interleukin 2

Abstract Because T lymphocytes and natural killer (NK) cells produce a variety of growth factors and interleukin 2 (IL2) modulates the activity of both, we assessed the ability of IL2 to stimulate human T cells and NK cells to produce hematopoietic growth factors detectable in clonogenic marrow culture. Human recombinant interleukin 2 (rIL2) added directly to cultures of human bone marrow that had been depleted of monocytes or depleted of both monocytes and T cells caused no significant alteration of myeloid (CFU-GM) or erythroid colony formation. Conditioned media harvested from rIL2-stimulated (greater than 100 U/mL) peripheral blood mononuclear cells, T cells, Leu-2 cells, and Leu-3 cells all had erythroid burst-promoting activity (BPA) but lacked myeloid colony- stimulating factor (GM-CSF) or CFU-GM-inhibitory activity. These T cells were IL2 receptor-negative, and the addition of anti-IL2 receptor monoclonal antibody (anti-Tac) to T cell cultures did not abrogate this IL2-stimulated BPA production. In addition, Percoll gradient-enriched, large granular lymphocytes (LGL) were separated by fluorescence- activated cell sorting into Leu-11+ (NK) cells and Leu-11- (low-density Leu-4+ T) cell fractions. rIL2 stimulated LGL, Leu-11+ and Leu-11- cells to produce BPA but not detectable GM-CSF or CFU-GM-inhibitory activity. Leu-11+ (NK) cells were Tac-negative from days 0 through 14 of culture. We conclude that rIL2 at high concentrations stimulated T cells, Leu-2 and Leu-3 cell subsets, LGL, and NK cells to produce BPA but not GM-CSF and that this stimulation may be mediated by an IL2 receptor distinct from Tac or by an epitope of the IL2 receptor not recognized by the anti-Tac antibody.

719 CD122-directed interleukin-2 complexes and αPD-L1 differentially require innate and adaptive immunity to treat local and metastatic bladder cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A761-A761
Author(s):  
Ryan Reyes ◽  
Yilun Deng ◽  
Deyi Zhang ◽  
Niannian Ji ◽  
Neelam Mukherjee ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
San Antonio ◽  
Interleukin 2 ◽  
Γδ T Cells ◽  
List Type ◽  
Γδ T Cell

BackgroundαPD-L1 bladder cancer (BC) immunotherapy is effective in <30% of cases.1 To address the large αPD-L1-unresponsive subset of patients, we tested αIL-2/IL-2 complexes (IL-2c) that block IL-2 from binding high-affinity IL-2Rα (CD25) for preferential IL-2Rβ (CD122) binding.2 Immunosuppressive regulatory T cells capture IL-2 by CD25 whereas antitumor CD8+ T, γδ T, and NK cells use CD122. We hypothesized that the tumor microenvironment, including local immune cells in primary versus metastatic BC, differentially affects immunotherapy responses and that IL-2c effects could differ from, and thus complement αPD-L1.MethodsWe used PD-L1+ mouse BC cell lines MB49 and MBT-2, for orthotopic, intravesical (i.e., in bladder) and intravenous challenge studies of local versus lung metastatic BC.ResultsαPD-L1 or IL-2c alone reduced tumor burden and extended survival in local MB49 and MBT-2. Using in vivo cell depletions, we found that γδ T cells and NK cells, but strikingly not CD8+ T cells, were necessary for IL-2c efficacy in bladder. We confirmed γδ T cell requirements for IL-2c, but not αPD-L1 efficacy in γδ T cell-null TCRδKO mice. TCRβKO conventional T cell-null mice exhibited IL-2c, but not αPD-L1 responsiveness for orthotopic BC treatment. Neither agent alone treated lung metastatic MB49 or MBT-2 but the drug combination improved survival in both tumor models. Combination treatment effects in lungs were distinct from bladder, requiring CD8+ T and NK cells, but not γδ T cells.ConclusionsBC immunotherapy effects differ by anatomic compartment and use distinct mechanisms to treat primary and metastatic BC. CD122-directed IL-2 is a promising BC immunotherapy strategy, and IL-2c is a candidate mediator through innate immune effects. αPD-L1 could improve IL-2c efficacy by engagement of adaptive immune responses including to improve metastatic disease treatment efficacy.Ethics ApprovalAll procedures involving animals in this study were approved by the UT Health San Antonio Institutional Animal Care and Use Committee (IACUC) and conducted in accordance with UT Health San Antonio Department of Laboratory Animal Resources standards.ReferencesShah AY, Gao J, Siefker-Radtke AO. Five new therapies or just one new treatment? A critical look at immune checkpoint inhibition in urothelial cancer: Future Medicine, 2017.Arenas-Ramirez N, Zou C, Popp S, et al. Improved cancer immunotherapy by a CD25-mimobody conferring selectivity to human interleukin-2. Science translational medicine 2016;8(367):367ra166-367ra166.

A Prospective Evaluation of the Effects of Extracorporeal Photopheresis on Important Immunological Markers in Chronic Graft Versus Host Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5125-5125
Author(s):  
John Bladon ◽  
Peter C. Taylor
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Chronic Gvhd ◽  
Extracorporeal Photopheresis ◽  
Graft Versus Host ◽  
Testing Stage

Abstract A major complication of allogeneic bone marrow or stem cell transplantation is the development of acute and chronic graft versus host disease (GvHD). Initial treatment includes corticosteroids and immunosuppressive agents. However, for steroid-refractory patients other non-conventional therapies are utilised. Recently, extracorporeal photopheresis (ECP) has shown efficacy for the treatment of acute and chronic GvHD unresponsive to standard therapy. ECP involves exposing white cells, harvested by selective leucopheresis, to 8 methoxypsoralen (8-MOP) and UVA light. The irradiated white cells are subsequently re-infused. The aetiology of GvHD involves the stimulation of proinflammatory cytokines; the levels of tumour necrosis factor alpha (TNFα) and Interferon gamma (IFNγ) have been closely linked to GvHD progression. The successful treatment of GvHD has also demonstrated changes in the ratio of CD4/CD8 T cells. The T-cell activation marker CD134 (OX40) has been observed in rats experiencing acute GvHD (aGvHD) and indicated to be a marker of steroid resistant acute and chronic GvHD. Natural Killer (NK) cells are believed to play an active role in suppressing GvHD. NK activity can be reduced in chronic GvHD (cGvHD) and animal models demonstrate GvHD suppression following NK cell transfer. Inhibitory natural killer cell receptors (NKRs) on NK cells can regulate NK and T cell function, including down-regulating target cell lysis. High levels of the NKR CD94 has been observed on patients without cGvHD. This prospective study was designed to determine if peripheral immunophenotypic markers associated with cGvHD are significantly altered by long term ECP therapy. New cGvHD referrals were tested prior to beginning therapy (0 months) and after 3, 6 and 12 months of treatment. On each occasion peripheral blood were tested for: CD4+, CD8+, CD4+/CD134+, CD8+CD134+, CD3+/CD94+, CD8+/CD94+, CD3−/CD56+ (NK), CD3+/IFNγ+, CD3+/TNFα and CD14+/TNFα. For 0–3 months n=16, for 0–6 months n=9 and for 0–12 months n=5. From 0–3 months a fall (p=0.031) in CD8 levels was observed, whilst CD4+ T cells increased from 0–12 months (p=0.040). At each testing stage an increase in the ratio of CD4/CD8 was observed, although these changes were not statistically significant. The percentage of CD4+/CD134+ and CD8+/CD134+ T cells decreased at each subsequent test, however significance was only observed between 0 and 12 months (p= 0.018 for both). NK cells (CD3−/CD56+) increased at 3, 6 and 12 months, however significance was only detected at 3 months (p=0.038). The percentage of CD3+ and CD8+ T cells expressing CD94 remained unchanged. A fall in T cells positive for IFNγ was observed at 3 months (p=0.047), however at each other testing stage the levels of CD3+/IFNγ+, CD3+/TNFα and CD14+/TNFα showed no significant change. Therefore, although increases in CD4/CD8 have been observed in cGvHD treated by ECP, this response remains controversial with many reports demonstrating conflicting data. Reduction of CD134 was observed following ECP, however at the tradition evaluation stage of 3 months no significant difference was observed. The levels of NK cells increased, consistent with previous reports, however CD94 expression was unaltered by ECP therapy. In the absence of a consistent phenotypic marker to demonstrate cGvHD response to ECP, continued monitoring will be based on clinical observations.

scholarly journals Analysis of the linker for activation of T cells and the linker for activation of B cells in natural killer cells reveals a novel signaling cassette, dual usage in ITAM signaling, and influence on development of the Ly49 repertoire

Blood ◽  
2008 ◽  
Vol 112 (7) ◽  
pp. 2869-2877 ◽  
Author(s):  
Gillian C. Whittaker ◽  
Deborah N. Burshtyn ◽  
Selinda J. Orr ◽  
Laura Quigley ◽  
Deborah L. Hodge ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Fine Tuning ◽  
Receptor Coupling ◽  
Integral Proteins ◽  
Activation Motif

AbstractThe linker for activation of T cells (LAT) and the linker for activation of B cells (LAB/NTAL/LAT2) are integral proteins in receptor coupling to downstream events. Both proteins are expressed in natural killer (NK) cells and LAT is phosphorylated during target cell interactions or ligation of the immunoreceptor tyrosine-based activation motif (ITAM)–coupled CD16. Regardless, Lat−/− mice exhibit normal natural and antibody-mediated killing. Here we place both LAT and LAB in the DAP12 pathway of NK cells. Moreover, we unveil a LAT-independent pathway that requires expression of Syk. Mice lacking either LAT or LAB have a skewed Ly49 repertoire, and activated NK cells from Lat−/− mice have reduced responses to the ITAM-coupled receptor NK1.1. In contrast, resting Lat−/− NK cells show intact NK1.1 responses, whereas NK cells without LAB are hyperactive. Elimination of both adaptors severely reduces NK1.1 signaling under both conditions. Together these data show that NK ITAMs preferentially use a signaling cassette regulated by interplay between LAT and LAB. Activation by interleukin-2 causes a shift to greater dependency on LAT due to suppression of Syk signaling. The overlapping use of multiple adaptors permits fine-tuning of NK-cell ITAM responses over the course of an immune response.

scholarly journals INFLUENCE OF REGULATORY T CELLS ON THE FUNCTIONING OF NATURAL KILLER CELLS DURING CANCER IMMUNOTHERAPY

2012 ◽  
Vol 67 (4) ◽  
pp. 60-64
Author(s):  
I. O. Chikileva ◽  
I. Zh. Shubina ◽  
E. V. Kiselevskii
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Natural Killer ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
Foxp3 Expression ◽  
Peripheral Blood Mononuclear ◽  
The Common

One of the common arguments against cancer immunotherapy based on natural killer (NK) cells activated in the presence of interleukin-2 (IL-2) is the probability of the activation of regulatory T cells (Tregs) by IL-2 besides NK cells. Thus, we have monitored numbers of FoxP3+CD4+CD25+ T cells in the samples of healthy volunteers’ peripheral blood mononuclear cells (PBMCs) cultured with or without IL-2. We observed marked increase in the percentages of the CD4+CD25+ T cells in the presence of IL-2. Proportions of Foxp3+CD4+CD25+ T cells feebly increased, remained on the same level or even decreased compared to PBMCs cultured without exogenous IL-2. Based on the absence of FoxP3 expression, most of the CD4+CD25+ T cells purified from IL-2 activated PBMCs were not Tregs, but activated Th cells. Moreover, the addition of the purified supposed Tregs to samples of activated NK cells never inhibited their cytotoxic reactions. 

scholarly journals CD94 1A transcripts characterize lymphoblastic lymphoma/leukemia of immature natural killer cell origin with distinct clinical features

Blood ◽  
2005 ◽  
Vol 106 (10) ◽  
pp. 3567-3574 ◽  
Author(s):  
Chung-Wu Lin ◽  
Ting-Yun Liu ◽  
Shee-Uan Chen ◽  
Kun-Teng Wang ◽  
L. Jeffrey Medeiros ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Lineage ◽  
Lymphoid Cells ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Gene Rearrangements

AbstractMost lymphoblastic lymphomas (LBLs) are regarded as neoplasms of immature T cells because they express cytoplasmic CD3 and frequently carry T-cell receptor (TCR) gene rearrangements. Immature natural killer (NK) and T cells, however, have a common bipotent T/NK-cell precursor in the thymus, and NK cells also express cytoplasmic CD3. Thus, some LBLs could arise from immature NK cells. Mature NK cells express 2 CD94 transcripts: 1A, induced by interleukin 15 (IL-15), and 1B constitutively. Because immature NK cells require IL-15 for development, CD94 1A transcripts could be a marker of NK-LBL. To test this hypothesis, we used laser capture microdissection to isolate IL-15 receptor α+ lymphoid cells from the thymus and showed that these cells contained CD94 1A transcripts. We then assessed for CD94 transcripts in 21 cases of LBL that were cytoplasmic CD3+, nuclear terminal deoxynucleotidyl transferase positive (TdT+), and CD56-, consistent with either the T-cell or NK-cell lineage. We found that 7 LBLs expressed CD94 1A transcripts without TCR gene rearrangements, suggesting NK-cell lineage. Patients with NK-LBL were younger than patients with T-LBL (15 years versus 33 years; P = .11) and had a better 2-year survival (100% versus 27%; P &lt; .01). These results improve the current classification of LBL and contribute to our understanding of NK-cell differentiation.

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