Increased Natural Killer Cells Are Associated with Alcohol Liver Fibrosis and with T Cell and Cytotoxic Subpopulations Change

Natural killer (NK) cells play a therapeutic role in liver fibrosis (LF). We aimed to analyze NK cells in heavy drinkers without cirrhosis or decompensated liver disease and establish correlations with other related subpopulations. Data on sociodemographic characteristics, alcohol consumption, laboratory parameters, and immunophenotyping of NK (CD16+/CD56+), T (CD3+), B (CD19+), NKT (CD16+/CD56+/CD3+), and cytotoxic (CD3-CD8+) cells were collected. Fibrosis-4 (FIB-4) scores were used to compare patients without (FIB-4 < 1.45) and with (FIB-4 > 3.25) advanced LF (ALF). We included 136 patients (76% male) with a mean age of 49 years who had a 15-year alcohol use disorder (AUD) and alcohol consumption of 164 g/day. Patients with ALF (n = 25) presented significantly lower absolute total lymphocyte, T cell, B cell, and NKT cell numbers than patients without LF (n = 50; p < 0.01). However, the NK cells count was similar (208 ± 109 cells/µL vs. 170 ± 105 cells/µL) in both groups. The T cells percentage was lower (80.3 ± 5.6% vs. 77 ± 7%; p = 0.03) and the NK cells percentage was higher (9.7 ± 5% vs. 13 ± 6%; p = 0.02) in patients with ALF than in those without LF. The percentages of NK cells and T cells were inversely correlated in patients without (r = –0.65, p < 0.01) and with ALF (r = −0.64; p < 0.01). Additionally, the NK cells and CD3-CD8+ cell percentages were positively correlated in patients without (r = 0.87, p < 0.01) and with (r = 0.92; p < 0.01) ALF. Conclusions: Heavy drinkers without decompensated liver disease showed an increase in NK cells related to T cells lymphopenia and an increase in cytotoxic populations. The interaction of NK cells with other subpopulations may modify alcohol-related liver disease progression.

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T Cell Subsets and Natural Killer Cells in the Pathogenesis of Nonalcoholic Fatty Liver Disease

International Journal of Molecular Sciences ◽

10.3390/ijms222212190 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12190

Author(s):

Yoseph Asmelash Gebru ◽

Haripriya Gupta ◽

Hyeong Seop Kim ◽

Jung A. Eom ◽

Goo Hyun Kwon ◽

...

Keyword(s):

T Cells ◽

Liver Disease ◽

T Cell ◽

Fatty Liver ◽

Nk Cells ◽

Nonalcoholic Fatty Liver Disease ◽

Natural Killer ◽

Fatty Liver Disease ◽

T Cell Subsets ◽

Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by hepatic accumulation of excess lipids. T cells are commonly classified into various subsets based on their surface markers including T cell receptors, type of antigen presentation and pathophysiological functions. Several studies have implicated various T cell subsets and natural killer (NK) cells in the progression of NAFLD. While NK cells are mainly components of the innate hepatic immune system, the majority of T cell subsets can be part of both the adaptive and innate systems. Several studies have reported that various stages of NAFLD are accompanied by the accumulation of distinct T cell subsets and NK cells with different functions and phenotypes observed usually resulting in proinflammatory effects. More importantly, the overall stimulation of the intrahepatic T cell subsets is directly influenced by the homeostasis of the gut microbiota. Similarly, NK cells have been found to accumulate in the liver in response to pathogens and tumors. In this review, we discussed the nature and pathophysiological roles of T cell subsets including γδ T cells, NKT cells, Mucosal-associated invariant T (MAIT) cells as well as NK cells in NAFLD.

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

Journal of Virology ◽

10.1128/jvi.00435-15 ◽

2015 ◽

Vol 89 (12) ◽

pp. 6435-6441 ◽

Cited By ~ 9

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.

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

Blood ◽

10.1182/blood.v104.11.5125.5125 ◽

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.

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

Blood ◽

10.1182/blood-2005-02-0519 ◽

2005 ◽

Vol 106 (10) ◽

pp. 3567-3574 ◽

Cited By ~ 15

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 < .01). These results improve the current classification of LBL and contribute to our understanding of NK-cell differentiation.

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Abstract P216: Inhibition Of T Cell Activation In Response To Placental Ischemia During Pregnancy Improves Hypertension And Activation Of Natural Killer Cells

Hypertension ◽

10.1161/hyp.76.suppl_1.p216 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Nathan Campbell ◽

Evangeline M Deer ◽

Lorena M Amaral ◽

Kristen Reeve ◽

Sarah Fitzgerald ◽

...

Keyword(s):

Blood Pressure ◽

T Cells ◽

T Cell ◽

Nk Cells ◽

Natural Killer ◽

T Cell Activation ◽

T Helper Cells ◽

Cell Activation ◽

T Helper ◽

Placental Ischemia

Preeclampsia (PE), new onset hypertension during pregnancy, is the leading cause of death and morbidity world-wide for the mother and fetus during pregnancy. The Reduced Uterine Perfusion Pressure Rat Model of PE (RUPP) exhibits many characteristics of PE including hypertension, suppressed regulatory T cells (T RegS ) associated with increased CD4+ T cells and B cells secreting agonistic autoantibodies to the AngII receptor (AT1-AA). We have previously shown that blockade of T-helper cells improves blood pressure and lowers AT1-AA secretion. A potential mechanism for the decreased blood pressure is decreased cytolytic natural killer (cNK) cells. Abatacept (Aba) is a fusion molecule designed to inhibit T cell co-stimulation in response to antigens and is used to treat autoimmune diseases. We hypothesize that treatment with Aba will prevent the activation of T-helper cells and therefore lower AT1-AA as a mechanism leading to less cNK cells in response to placental ischemia in RUPP rats. Aba was given on day 13 via the jugular vein. On day 19, blood and tissues were collected, blood pressure (MAP), pup weight, and NK cells were measured by flow cytometry in the blood and placenta. A one-way ANOVA was used for statistical analysis. On GD19, MAP significantly increased in RUPP 119±2 mmHg (n=7, p<0.05) compared to NP controls 102±2 mmHg (n=7) and was normalized with Aba (100±2 mmHg (n=10, p<0.05). Compared to the NP controls (2.2±0.06, n=7), pup weight significantly decreased in RUPP (2±0.08, n=7, p<0.05) but was 2± 0.07, with Aba (n=10). Circulating and placental total NK cells were 32±5, 44±13, % gate in NP rats (n=7), 59±4, 60±16 % gate in RUPP rats (n=7, p<0.05; n=4), which significantly decreased to 40±6, 28±8 % gate with Aba (n=10, p<0.05; n=11). Our findings indicate that prevention of T cell activation lowers total NK cell number and blood pressure in response to placental ischemia of pregnancy.

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Clinical-Scale Combined CD4/CD8 Depletion for Donor Innate Lymphocyte Infusion (DILI).

Blood ◽

10.1182/blood.v108.11.3657.3657 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3657-3657

Author(s):

Volker Kunzmann ◽

Manfred Smetak ◽

Florian Weissinger ◽

Josef Birkmann ◽

Hermann Einsele ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Nk Cells ◽

Γδ T Cells ◽

Innate Immune ◽

Clinical Scale ◽

Cell Recovery ◽

Cd8 Cells ◽

Cd8 Depletion

Abstract The ability to selectively deplete or enrich cells of specific phenotype by immunomagnetic selection procedures holds significant promise for application in adoptive immunotherapy protocols. In vitro and in vivo studies demonstrated that MHC-independent effector cells of the innate immune system such as natural killer (NK) cells and γδ T cells have potent anti-tumor activity without inducing Graft-versus-Host disease (GvHD). However, current clinical-scale approaches to reduce the risk of GvHD usually use T-cell depletion (such as CD34+ selection or CD3+ depletion). However, both procedures also deplete γδ T cells which may be advantageous in mediating Graft-versus tumor effects and augmenting innate immune response against infections. Here we present a new method for depletion of T cells with potential GvHD reactivity and simultaneously enrichment of innate lymphocytes (NK cells and γδ T cells) from standard leukapheresis products by using a single-step immunomagnetic protocol which efficiently depletes CD4+ and CD8+ αβ T cells under good manufacturing conditions (GMP). Efficiency of CD4+ and CD8+ T cell depletion from (unstimulated) leukapheresis products (n=6) containing up to 2.0 × 1010 white blood cells, was demonstrated by 4-color flow cytometric analysis (mean log depletion of CD4+ cells: 4.12 (3.17–4.9); mean log depletion of CD8+ cells: 3.77 (2.97–4.54)). In addition to efficient depletion of CD4+ and CD8+ cells, immunomagnetic CD4/CD8 depletion resulted in enrichment of NK cells and γδ T cells (mean NK cell recovery: 38%(19–72), mean γδ T cell cell recovery: 50%(34–79)). In vitro assays of the final product demonstrated that NK cells and γδ T cells preserved their proliferative and cytotoxic capacity. We conclude that simultaneous depletion of CD4+ and CD8+ cells is feasible and can be performed in large scale under GMP conditions with sufficient depletion efficacy of αβ T cells and recovery of functionally intact innate effector lymphocytes (NK cells and γδ T cells) for potential use in adoptive immunotherapy studies.

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CMV-Specific Cytokine-Induced Killer Cells Comprise Concomitant Cytotoxicity Against Leukemia and Cytomegalovirus

Blood ◽

10.1182/blood.v124.21.5814.5814 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5814-5814

Author(s):

Verena Pfirrmann ◽

Sarah Oelsner ◽

Eva Rettinger ◽

Sabine Huenecke ◽

Jindrich Cinatl ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Nk Cells ◽

Nk Cell ◽

Cell Receptor ◽

Effector Memory ◽

Cd8 Cells ◽

Cik Cells ◽

Leukemic Relapse ◽

Ifn Γ

Abstract Introduction Infection is one of the main causes of mortality and morbidity after allogeneic stem cell transplantation, especially in patients who received T cell depleted haploidentical stem cells. Reactivation or de novo infection of cytomegalovirus (CMV) is amongst the most frequent complications and occur due to a lack of virus-specific T cells post-transplant. Pre-emptive immunotherapy may support both reconstitution of viral specific responses on one hand and may prevent impending leukemic relapse on the other hand. Therefore we established a protocol to generate CMV-specific cytokine-induced killer cells (CIKpp65) with dual cytolytic function against CMV and AML. Protocol CIK cells were generated in vitro from peripheral blood mononuclear cells (PBMC) of CMV-seropositive healthy donors using IFN-γ, activating monoclonal anti-CD3 antibody (MAb), interleukin (IL)-2 and IL-15. An additional single stimulation with human CMVpp65 protein was adequate to increase the amount of cytotoxic CMV-specificcells within CIK cells up to 23%. In total the CMVpp65 stimulation resulted in up to 11.0-fold increased frequency of CMV-dextramer+CD8+cells after 15 days of expansion (n=12). Results Cytotoxicity Next we investigated cell-mediated cytotoxicity against leukemic cell lines THP-1 and K562, pp65 loaded cell line T2 and CMV-infected primary fibroblasts. CIK cell cytotoxicity is described as mediated by activating NK-cell receptor NKG2D. This receptor was blocked in order to determine the specific MHC-mediated cytotoxicity in experiments targeting pp65 loaded cells. The lysis of pp65 loaded cells by CIKpp65 cells was significant higher as compared to conventional CIK cells (effector to target cell ratio of 5:1, 39.9±21.6% to 13.6±10.6%, P<0.01). CIKpp65 cells also induced high cytotoxicity in infected fibroblasts (up to 55%, 10:1 E:T ratio). The anti-leukemic effect was retained in CIKpp65 cells. CIKpp65 cells revealed a mean cytotoxicity of 71.5%, 60.7% and 37.8% against THP-1 and 55.0%, 50.0%, 20.5% against K562 in 40:1, 20:1 and 5:1 E:T ratio, respectively. In contrast, the reactivity against allogeneic PBMC remained low (18% lysis, 40:1 E:T ratio) and allogeneic mock-infected fibroblasts were not lysed at all. This clearly indicates towards the low alloreactive potential of CIKpp65 cells. Phenotype Furthermore we characterized subpopulation and memory phenotype of CIKpp65 cells in detailed flow cytometric analyses and examined the cytokine secretion pattern by cytometric bead array. After expansion the population mainly consisted of a CD3+CD56- T cell (77.6±4.5%) and CD3+CD56+ T-NK cell phenotype (20.0±12.6%). The T-NK cells additionally co-expressed high amounts of CD8 cytotoxic antigen (63.8±16.8%). Interestingly, the T-NK cell compartment contained higher amounts CMV-specific CD8+ cells (mean 5.5%) than the T cell compartment (mean 1.3%). Expression of activating NKG2D and CD25 receptor was strongly positive in both cell fractions. Remarkably, almost 30% of T-NK cells expressed γδ+ T cell receptor, whereas T cells only expressed 4.5% of this receptor type. The cytotoxic T cells within the CIKpp65 cells consisted of a mixed naïve (CD45RA+CD62L+), central memory (CD45RO+CD62L+) and effector memory (CD45RO+CD62L-) phenotype, the cytotoxic T-NK cells mainly of effector memory and EMRA (CD45RA+CD62L-) phenotype. Cytokine secretion (granzyme B, IFN-γ, MIP-1α, TNF-α, Fas-L, IP-10, IL-10, IL-6 and IL-4) were measured during the expansion period and cytotoxic assays and resulting data confirmed the cytotoxic nature of the cells and indicated towards a mainly TH1 cell type character. Conclusion In conclusion CIKpp65 cells can easily be generated from donor PBMC and might represent advantage to conventional CIK cells. Our pre-clinical data demonstrate the concomitant cytotoxicity of generated cells against leukemia cells and CMV, as well as low alloreactivity and limited risk to induce GvHD. Therefore CIKpp65 cells may represent an effective tool for pre-emptive immunotherapy in patients which have both an apparent risk of CMV reactivation and leukemic relapse after allogeneic stem cell transplantation. Disclosures No relevant conflicts of interest to declare.

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The Transcription Factor Interferon Regulatory Factor 1 (IRF-1) Is Important during the Maturation of Natural Killer 1.1+ T Cell Receptor–α/β+ (NK1+ T) Cells, Natural Killer Cells, and Intestinal Intraepithelial T Cells

Journal of Experimental Medicine ◽

10.1084/jem.187.6.967 ◽

1998 ◽

Vol 187 (6) ◽

pp. 967-972 ◽

Cited By ~ 137

Author(s):

Toshiaki Ohteki ◽

Hiroki Yoshida ◽

Toshifumi Matsuyama ◽

Gordon S. Duncan ◽

Tak W. Mak ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Nk Cells ◽

Natural Killer ◽

T Cell Receptor ◽

Lymphocyte Subsets ◽

Cell Receptor ◽

Interferon Regulatory Factor ◽

Regulatory Factor ◽

Interferon Regulatory Factor 1

In contrast to conventional T cells, natural killer (NK) 1.1+ T cell receptor (TCR)-α/β+ (NK1+T) cells, NK cells, and intestinal intraepithelial lymphocytes (IELs) bearing CD8-α/α chains constitutively express the interleukin (IL)-2 receptor (R)β/15Rβ chain. Recent studies have indicated that IL-2Rβ/15Rβ chain is required for the development of these lymphocyte subsets, outlining the importance of IL-15. In this study, we investigated the development of these lymphocyte subsets in interferon regulatory factor 1–deficient (IRF-1−/−) mice. Surprisingly, all of these lymphocyte subsets were severely reduced in IRF-1−/− mice. Within CD8-α/α+ intestinal IEL subset, TCR-γ/δ+ cells and TCR-α/β+ cells were equally affected by IRF gene disruption. In contrast to intestinal TCR-γ/δ+ cells, thymic TCR-γ/δ+ cells developed normally in IRF-1−/− mice. Northern blot analysis further revealed that the induction of IL-15 messenger RNA was impaired in IRF-1−/− bone marrow cells, and the recovery of these lymphocyte subsets was observed when IRF-1−/− cells were cultured with IL-15 in vitro. These data indicate that IRF-1 regulates IL-15 gene expression, which may control the development of NK1+T cells, NK cells, and CD8-α/α+ IELs.

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Human natural killer cell committed thymocytes and their relation to the T cell lineage.

Journal of Experimental Medicine ◽

10.1084/jem.178.6.1857 ◽

1993 ◽

Vol 178 (6) ◽

pp. 1857-1866 ◽

Cited By ~ 78

Author(s):

M J Sánchez ◽

H Spits ◽

L L Lanier ◽

J H Phillips

Keyword(s):

T Cells ◽

T Cell ◽

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Cell Lineage ◽

Surface Expression ◽

Cd34 Cells ◽

Clonogenic Potential ◽

Antigenic Phenotype

Recent studies have demonstrated that mature natural killer (NK) cells can be grown from human triple negative (TN; CD3-, CD4-, CD8-) thymocytes, suggesting that a common NK/T cell precursor exists within the thymus that can give rise to both NK cells and T cells under appropriate conditions. In the present study, we have investigated human fetal and postnatal thymus to determine whether NK cells and their precursors exist within this tissue and whether NK cells can be distinguished from T cell progenitors. Based on the surface expression of CD56 (an NK cell-associated antigen) and CD5 (a T cell-associated antigen), three phenotypically distinctive populations of TN thymocytes were identified. CD56+, CD5-; CD56-, CD5-, and CD56-, CD5+. The CD56+, CD5- population of TN thymocytes, although displaying a low cytolytic function against NK sensitive tumor cell targets, were similar in antigenic phenotype to fetal liver NK cells, gave rise to NK cell clones, and were unable to generate T cells in mouse fetal thymic organ cultures (mFTOC). This population of thymocytes represents a relatively mature population of lineage-committed NK cells. The CD56-, CD5- population of TN thymocytes were similar to thymic NK cells in antigenic phenotype and NK cell clonogenic potential. Clones derived from this population of TN thymocytes acquired CD56 surface expression and NK cell cytolytic function. CD56-, CD5- TN thymocytes thus contain a novel population of NK cell-committed precursors. The CD56-, CD5- population of TN thymocytes also contains a small percentage of CD34+ cells, which demonstrate no in vitro clonogenic potential, but possess T cell reconstituting capabilities in mFTOC. The majority of TN thymocytes do not express CD56, but coexpress CD34 and CD5. These CD56-, CD5+, CD34+ cells demonstrate no NK or T cell clonogenic potential, but are extremely efficient in repopulating mFTOC and differentiating into CD3+, CD4+, CD8+ T cells. The results of this investigation have identified NK cells and NK cell precursors in the human thymus and have shown that these cell types are unable to differentiate along the T cell lineage pathway. Thus, while a common NK/T cell progenitor likely exists, once committed to the NK cell lineage these cells no longer have the capacity to develop along the T cell developmental pathway.

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Signal transduction by the CD2 antigen in T cells and natural killer cells: requirement for expression of a functional T cell receptor or binding of antibody Fc to the Fc receptor, Fc gamma RIIIA (CD16).

Journal of Experimental Medicine ◽

10.1084/jem.174.6.1407 ◽

1991 ◽

Vol 174 (6) ◽

pp. 1407-1415 ◽

Cited By ~ 33

Author(s):

L L Spruyt ◽

M J Glennie ◽

A D Beyers ◽

A F Williams

Keyword(s):

Signal Transduction ◽

T Cells ◽

T Cell ◽

Nk Cells ◽

Natural Killer ◽

T Cell Receptor ◽

Nk Cell ◽

Cell Receptor ◽

Fc Receptor ◽

Jurkat Cells

Crosslinking of CD2 antigen on T lymphocytes and natural killer (NK) cells leads to a rise in cytoplasmic-free Ca2+ concentration ([Ca2+]i). However, CD2 seems unlikely to interact directly with the second messenger pathways since signaling via CD2 is poor in T cells that lack the T cell receptor (TCR) and is absent in L cells or insect cells that express CD2. In contrast, NK cells that are also TCR- can be triggered via CD2, but it is unclear as to whether the CD16 Fc receptor (FcR) may facilitate this effect. The CD16 transmembrane molecule is expressed in a complex with the zeta homodimer or the zeta/gamma heterodimer and these dimers are also associated with the TCR complex. Thus, it seemed that zeta chains may provide the link between signaling on NK cells and T cells. This could be tested on TCR- cells since when CD16 is transfected into T cells it is expressed in a complex with TCR zeta homodimer or the zeta/gamma heterodimer. At first, potentiation of CD2 signaling was seen on TCR- Jurkat cells expressing CD16, but this was found to be dependent on trace levels (1%) of IgG in F(ab')2 antibody preparations. With pure F(ab')2, the effect was lost. Signaling on a rat NK cell line was also re-examined with F(ab')2 antibodies that had no IgG contamination, and again no signal transduction via CD2 was seen. We thus conclude that there is no clear evidence for potent signaling via CD2 on cells that lack a TCR complex and that TCR zeta chain expressed at the cell surface is not sufficient to potentiate signaling via CD2 as measured by an increase in [Ca2+]i.

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