scholarly journals CD16ahigh NK cell infiltration and spatial relationships with T cells and macrophages can predict improved progression-free survival in high grade ovarian cancer

2021 ◽  
Author(s):  
Sarah Nersesian ◽  
Stacey N Lee ◽  
Stephanie Grantham ◽  
Liliane Meunier ◽  
Laudine Communal ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Immune Cell ◽  
Nk Cell ◽  
Cell Subset ◽  
Progression Free Survival ◽  
High Grade ◽  
Free Survival ◽  
Adaptive Immune ◽  
Adaptive Immune Cell

Background: High grade serous cancer (HGSC) remains a highly fatal malignancy with less than 50% of patients surviving 5 years after diagnosis. Despite its high mutational burden, HGSC is relatively refractory to checkpoint immunotherapy, suggesting that additional features of the cancer and its interactions with the immune system remain to be understood. Natural killer (NK) cells may contribute to HGSC control, but the role(s) of this population or its subsets in this disease are poorly understood. Methods: We used a TMA containing duplicate treatment-naive tumors from 1145 patients with HGSC and a custom staining panel to simultaneously measure macrophages, T cells and NK cells, separating NK cells based on CD16a expression. Using pathologist-validated digital pathology, machine learning, computational analysis and Pearsons correlations, we quantitated infiltrating immune cell density, co-infiltration and co-localization with spatial resolution to tumor region. We compared the prognostic value of innate, general, and adaptive immune cell neighborhoods to define characteristics of HGSC tumors predictive for progression-free survival and used flow cytometry to define additional features of the CD16adim NK cell subset. Results: NK cells were observed in >95% of tumor cores. Intrastromal localization of CD16alow and CD16ahigh NK cells was associated with shorter and longer progression-free survival, respectively. CD16ahigh NK cells most frequently co-localized with T cells and macrophages; their proximity was termed an adaptive neighborhood. We find that tumors with more area represented by adaptive immune cell neighborhoods corresponded to superior progression free survival. In contrast, CD16alow NK cells did not co-infiltrate with other immune cell types, and expressed the ectonucleotidases, CD39 and CD73, which have been previously associated with poor prognosis in patients with HGSC. Conclusions: Progression-free survival for patients with HGSC may be predicted by the subset of NK cells within the tumor infiltrate (i.e. CD16ahigh vs. CD16alow). NK cell subtypes were associated predictable co-infiltrating and co-localizing leukocyte subsets, suggesting that their presence and activity may influence, or be influenced by the tumor microenvironment. Our data suggest that immunotherapeutic strategies for HGSC should consider the constitution of NK cell subsets and may benefit from mobilizing and activating CD16high NK cells.

scholarly journals IL-2–dependent tuning of NK cell sensitivity for target cells is controlled by regulatory T cells

2013 ◽  
Vol 210 (6) ◽  
pp. 1167-1178 ◽  
Author(s):  
Georg Gasteiger ◽  
Saskia Hemmers ◽  
Matthew A. Firth ◽  
Audrey Le Floc’h ◽  
Morgan Huse ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Nk Cells ◽  
Immune Cell ◽  
Nk Cell ◽  
Adaptive Immune System ◽  
Target Cells ◽  
Cell Reactivity ◽  
Adaptive Immune ◽  
Missing Self

The emergence of the adaptive immune system took a toll in the form of pathologies mediated by self-reactive cells. Regulatory T cells (T reg cells) exert a critical brake on responses of T and B lymphocytes to self- and foreign antigens. Here, we asked whether T reg cells are required to restrain NK cells, the third lymphocyte lineage, whose features combine innate and adaptive immune cell properties. Although depletion of T reg cells led to systemic fatal autoimmunity, NK cell tolerance and reactivity to strong activating self- and non-self–ligands remained largely intact. In contrast, missing-self responses were increased in the absence of T reg cells as the result of heightened IL-2 availability. We found that IL-2 rapidly boosted the capacity of NK cells to productively engage target cells and enabled NK cell responses to weak stimulation. Our results suggest that IL-2–dependent adaptive-innate lymphocyte cross talk tunes NK cell reactivity and that T reg cells restrain NK cell cytotoxicity by limiting the availability of IL-2.

scholarly journals Natural Killer Cells Are Present in Rag1−/− Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke

2021 ◽  
Author(s):  
Leoni Rolfes ◽  
Tobias Ruck ◽  
Christina David ◽  
Stine Mencl ◽  
Stefanie Bock ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Adoptive Transfer ◽  
Immune Cell ◽  
Nk Cell ◽  
Cell Subset ◽  
Neurological Deficits ◽  
In Vitro Assays ◽  
Experimental Stroke ◽  
Transfer Model

AbstractRag1−/− mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1−/− mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1nullIL2rgnull (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1−/− and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1−/− NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1−/− were comparable in number and function to those in WT mice. Rag1−/− mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1−/− controls. Our results indicate that NK cells from Rag1−/− mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke.

Real-Time Immunophenotyping of Peripheral Blood Early Post Myeloablative Cord Blood Transplant Can Identify Patients at Risk for Primary Graft Failure

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3897-3897
Author(s):  
Jianqiang Li ◽  
Filippo Milano ◽  
Joseph M Blake ◽  
David C. Oliver ◽  
Ian Nicoud ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Graft Failure ◽  
De Novo ◽  
Nk Cell ◽  
Cell Subset ◽  
Absolute Number ◽  
Hematopoietic Recovery ◽  
Primary Graft Failure ◽  
The Absolute

Abstract Introduction: Primary graft failure (PGF) is a potentially life threatening complication following hematopoietic cell transplantation. Patients undergoing cord blood transplantation (CBT) are at higher risk for PGF and also experience delayed hematopoietic recovery. The ability to distinguish between PGF and delayed engraftment is critical for correct clinical management. Limited data exists analyzing the kinetics of engraftment of specific circulating cell lineages within 14 days after double CBT (dCBT). Herein, we investigate the potential for real time immunophenotyping (RTIP) of day 7 and day 14 post-transplant peripheral blood (PB) samples as an effective and economically feasible tool to distinguish PGF versus delayed engraftment. Methods: Between Feb 2013 and Jun 2014, 26 patients underwent a myeloablative dCBT at our institute. Heparinized PB samples (30 ml) were obtained from patients on days 7 and 14 post-transplant. PB mononuclear cells (PBMCs) were isolated by density gradient separation and total cell number was counted. RTIP with 9-color flow cytometry was performed at each time point using isolated fresh PBMC. Results: Median time to engraftment was 19 days (range 12-51) in 23 evaluable patients. The remaining 3 patients had no documented hematopoietic recovery by routine daily CBCs. Two patients were declared PGFs when day 21 PB chimerism results demonstrated 100% host T cells followed by confirmation of 0% donor engraftment on day 28. The third patient never had sufficient quantity of circulating cells to obtain RTIP results and died on day 28 with no hematopoietic recovery. Excluding this patient, we were able to quantify the absolute number of PBMC at day 7 (median: 3.1/µl; 95% CI: 2.6-4.6) and day 14 (median: 26/µl; 95% CI: 33-103) in all other patients. There was an increase in the absolute number of PBMC from day 7 to 14 in all patients except the two who experienced PGF. Furthermore, RTIP of day 7 PBMC revealed a predominance of T cells that were donor-derived, while day 14 RTIP of PBMC demonstrated a decreased frequency of T cells and increased frequency of predominantly donor-derived monocytes and NK cells. In contrast to the engrafting patients, the two PGF patients displayed a markedly different pattern in RTIP with minimal evidence of circulating monocytes in the day 14 samples (Fig 1A). Importantly, RTIP demonstrated that day 7 PBMC contained a higher frequency of CD14+CD16- monocytes and CD56brightCD16- NK cells than were infused, suggesting these specific cells were generated de novo and were not representative of cells infused with the graft (data not shown). Correlations between day 7 or day 14 cell subset numbers and time to engraftment were analyzed. The median absolute number of monocytes at day 7 was 0.075/µl (95% CI: 0.03-0.153). Patients with day 7 monocyte counts above the median demonstrated earlier engraftment than patients below the median (17.5 vs 26.5 days; p= 0.011). Using linear regression with engraftment as the variable of interest and the absolute number of day 7 monocytes as the predictor, the coefficient was 0.6 (95% CI: 0.075- 0.78, P=0.025) (Fig 1B). As expected, higher day 14 monocytes also correlated with earlier engraftment. With respect to the NK cell subset, the absolute number of NK cells at day 7 was not significantly correlated with engraftment time, but day 14 NK cell numbers were predictive of engraftment kinetics. The median number of NK cells at day 14 was 2.78/µl (95% CI: 1.87-5.79). Patients with day 14 NK counts above the median had earlier engraftment than those below the median (16 vs 26.5 days; (P=0.0034). The regression coefficient was 0.5 (95% CI, 0.077- 0.77; P=0.024). Finally, although total T cell numbers at day 7 and day 14 had no correlation with engraftment time, the two evaluable PGF patients had a greater inversion of CD4:CD8 ratio (0.038 & 0.058) than others (median: 0.71, 95% CI: 0.22-1.42) at day 14. Conclusions: This study provides the first clear evidence that RTIP of PBMC at days 7 and 14 can detect the kinetics of circulating de novo generated monocytes and NK cells and also reflects the in vivo immune environment in patients following dCBT. Importantly, detecting and measuring specific cell subsets using RTIP permits earlier identification of patients at high risk of graft failure versus patients with delayed engraftment and warrants further development as a clinically feasible diagnostic method to guide clinical intervention. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Treatment of mice with IL2-complex enhances inflammasome-driven IFN-γ production and prevents lethal toxoplasmosis

2019 ◽  
Author(s):  
Andreas Kupz ◽  
Saparna Pai ◽  
Paul R. Giacomin ◽  
Jennifer A. Whan ◽  
Robert A. Walker ◽  
...  
Keyword(s):  
T Cells ◽  
Toxoplasma Gondii ◽  
Nk Cells ◽  
Immune Cell ◽  
Nk Cell ◽  
Severe Disease ◽  
Toxoplasmic Encephalitis ◽  
Parasite Invasion ◽  
Ifn Γ

AbstractToxoplasmic encephalitis is an AIDS-defining condition in HIV+individuals. The decline of IFN-γ-producing CD4+T cells in AIDS is a major contributing factor in reactivation of quiescentToxoplasma gondiito an actively replicating stage of infection. Hence, it is important to identify CD4-independent mechanisms to control acuteT. gondiiinfection. Here we have investigated the targeted expansion and regulation of IFN-γ production by CD8+T cells, DN T cells and NK cells in response toT. gondiiinfection using IL-2 complex (IL2C) pre-treatment in an acutein vivomouse model. Our results show that expansion of CD8+T cells, DN T cells and NK cell by S4B6 IL2C treatment increases survival rates of mice infected withT. gondiiand this increased survival is dependent on both IL-12- and IL-18-driven IFN-γ production. Processing and secretion of IFN-γ-inducing, bioactive IL-18 is dependent on the sensing of active parasite invasion by multiple redundant inflammasome sensors in multiple hematopoietic cell types but independent fromT. gondii-derived dense granule (GRA) proteins. Our results provide evidence for a protective role of IL2C-mediated expansion of CD8+T cells, DN T cells and NK cells in murine toxoplasmosis and may represent a promising adjunct therapy for acute toxoplasmosis.Author SummaryA third of the world’s population is chronically infected with the parasiteToxoplasma gondii. In most cases the infection is asymptomatic, but in individuals suffering from AIDS, reactivation of brain and muscle cysts containingT. gondiiis a significant cause of death. The gradual decline of CD4 T cells, the hallmark of AIDS, is believed to be a major contributing factor in reactivation ofT. gondiiinfection and the development of acute disease. In this study, we show that targeted expansion of non-CD4 immune cell subsets can prevent severe disease and premature death via increased availability of interferon gamma-producing immune cells. We also demonstrate that the upstream signaling molecule interleukin-18 is required for the protective immune response by non-CD4 cells and show that the sensing of active parasite invasion by danger recognition molecules is crucial. Our findings reveal that targeted cell expansion may be a promising therapy in toxoplasmosis and suggests that the development of novel intervention strategies targeting danger recognition pathways may be useful against toxoplasmosis, particularly in the context of AIDS.

LTBP2 Serves as a Prognostic Biomarker and Correlated with the Immune Infiltration in Stomach and Colon Cancer

2021 ◽  
Author(s):  
Shuai Chen ◽  
Zhihuai Wang ◽  
Yu Gong ◽  
Hanyang Liu ◽  
Haojun Yang ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Immune Cell ◽  
Disease Free Survival ◽  
Colon Adenocarcinoma ◽  
Progression Free Survival ◽  
Transforming Growth Factor Β ◽  
Gene Markers ◽  
Free Survival

Abstract Latent transforming growth factor β binding protein 2 (LTBP2) involved in the TGF pathway to induce immunosuppression and immune response. However, the association between the outcome of patients, the infiltrating immune cell and LTBP2 expression is still unclear in human cancers. The LTBP2 expression was analyzed by TIIMER and Oncomine database. Based on the Prognoscan database, the GEPIA database, and the Kaplan-Meier plotter database, the prognostic value was assessed. The immune and stromal score of tumors was calculated through ESTIMATE. We additionally explore the relationship among the LTBP2 expression, the infiltrating immune cells, and its gene markers in the TIMER, TISIDB, and GEPIA database, the enriched KEGG pathways of LTBP2 were evaluated by GSEA. The result showed that LTBP2 expressed differently among the normal and tumor tissues in various sorts of cancer involving stomach adenocarcinoma (STAD) and colon adenocarcinoma (COAD), and three cohorts of COAD presented that the LTBP2 high expression was linked with poorer disease-free survival and the elevated LTBP2 expression correlated with progression-free survival and poorer overall survival in STAD. The LTBP2 was correlated with the stromal and immune score in different cancers. The infiltrating immune cells include the CD8+T cells and CD4+T cells, macrophages, neutrophils, and dendritic cells were correlated with the LTBP2 expression. Meanwhile, LTBP2 was related to the infiltrating immune cell’s gene markers and enriched immune-related pathways in STAD and COAD. LTBP2 was the potential to be an independent predictor for the prognosis and a new target for immunotherapy in STAD and COAD.

Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1)

Blood ◽  
2002 ◽  
Vol 100 (10) ◽  
pp. 3698-3702 ◽  
Author(s):  
David Voehringer ◽  
Marie Koschella ◽  
Hanspeter Pircher
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Subset ◽  
Peripheral Blood Lymphocytes ◽  
Proliferative Potential ◽  
Proliferative Capacity ◽  
Effector T Cell ◽  
Proliferation Of Lymphocytes

Adaptive immunity necessitates the proliferation of lymphocytes. In the mouse, we have previously shown that antigen-experienced T cells that have lost their proliferative potential express the killer cell lectinlike receptor G1 (KLRG1). By using a newly generated monoclonal antibody specific for human KLRG1, we now demonstrate that expression of KLRG1 also identifies T cells in humans that are capable of secreting cytokines but that fail to proliferate after stimulation. Furthermore, our data show that proliferative incapacity of CD8 T cells correlates better with KLRG1 expression than with absence of the CD28 marker. In peripheral blood lymphocytes (PBLs) from healthy adult donors, KLRG1 was expressed on 44% ± 14% of CD8 and 18% ± 10% of CD4 T cells. KLRG1 expression was restricted to antigen-experienced T cells. Here, KLRG1+ cells were preferentially found in the CCR7− effector T-cell pool. Besides T cells, a significant portion (approximately 50%) of human natural killer (NK) cells expressed KLRG1. Interestingly, these KLRG1+ NK cells were found exclusively in the CD56dim NK-cell subset. Thus, the expression of KLRG1 identifies a subset of NK cells and antigen-experienced T cells in humans that lack proliferative capacity.

scholarly journals Low Blood Absolute CD4 Counts Is Associated with Inferior Progression Free Survival in Diffuse Large B-Cell Lymphoma Independent of Age and IPI

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5420-5420 ◽  
Author(s):  
Tahseen I. Al-Saleem ◽  
Essel Dulaimi ◽  
Michael M. Millenson ◽  
Mitchell R. Smith ◽  
Julia Judd ◽  
...  
Keyword(s):  
Immune Cell ◽  
Nk Cell ◽  
Cell Lymphoma ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Free Survival ◽  
Cell Counts ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Tumor-infiltrating immune cells influence diffuse large B-cell lymphoma (DLBCL) outcome. Relatively little is known about the significance of peripheral blood immune cell counts (obtained by generally available flow cytometry) on DLBCL behavior Patients and methods: 45 newly diagnosed DLBCL patients enrolled in an institutional protocol had blood pretreatment multicolor flow cytometry performed and immune cell counts recorded. The M/F ratio was 24/21, age 19-88, median 64; stage I: 11, II: 13, III: 6 and IV: 15. Thirty two had low/ intermediate International Prognostic Index (IPI) score (0-2) and 13 had 3+ IPI. One patient was HIV+. Thirty seven (82%) received immuno-chemotherapy and 8 had chemotherapy and/or irradiation. Statistical Methods: The outcomes of the study were progression free survival (PFS) and overall survival (OS). Kaplan-Meier estimation method and Log-rank test were used in the univariate analysis. The Cox proportional hazard model was used for multivariable analysis (MVA). All analyses were done via SAS 9.2. Results: Mean absolute CD4 cell count (ACD4C) was 450/c.mm and the median about 400. After follow up of 0.8 to 152 months (median: 73), 25 (56%) were still alive. Univariate analysis: significant predictors to PFS were: age (HR=1.05, 95%CI: 1.02-1.09, p=0.005), ACD4C (HR= 0.998, 95% CI: 0.966-1.000, p= 0.023] and IPI (HR=0.05, 95%CI: 0.995-1.89, p= 0.054). But for OS ACD4C was only marginally significant (p= 0.083). Absolute lymphocyte count (ALC), CD8 and [CD3-C56+ (NK)] counts did not correlate with OS or PFS. When analyzed as a binary variable with cutoff of 450/cmm, the 18 patients with high ACD4C had better 5 year PFS, 88% vs. 52% (p= 0. 023), figure (1), and OS, 88% vs. 59% (0.054) than the 27 with low ACD4C. Age, IPI groups (low /intermediate versus high) and ALC also correlated with PFS and OS, but not the CD8 or NK cell counts. MVA with age as a continuous variable, IPI groups and ACD4C of 450/cmm; age and ACD4C only were significant for PFS, (p= 0.008 and 0.036 respectively). For OS age was the only significant variable (p=0.017). ALC, CD8 and NK cell counts did not correlate with PFS or OS. Conclusion: Though the series contains more early stage patients than usual, blood ACD4C seems to be a predictor of PFS and to a lesser extent OS in DLBCL independent of age and IPI. If confirmed in a larger prospective study of uniformly treated patients ACD4C may serve as an immunological marker for DLBCL biological behavior. Figure1: Progression Free Survival Figure1:. Progression Free Survival Disclosures No relevant conflicts of interest to declare.

scholarly journals Analysis of adaptive immune cell populations and phenotypes in the patients infected by SARS-CoV-2

2020 ◽  
Author(s):  
Xiaofeng Yang ◽  
Tongxin Dai ◽  
Xiaobo Zhou ◽  
Hongbo Qian ◽  
Rui Guo ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Age Groups ◽  
Cell Populations ◽  
Adaptive Immune ◽  
Adaptive Immune Cell ◽  
Cell Percentage ◽  
Enhanced Expression ◽  
Functional Features

AbstractCoronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, has rapidly spread to most of countries in the world, threatening the health and lives of many people. Unfortunately, information regarding the immunological characteristics in COVID-19 patients remains limited. Here we collected the blood samples from 18 healthy donors (HD) and 38 COVID-19 patients to analyze changes in the adaptive immune cell populations and phenotypes. In comparison to HD, the lymphocyte percentage was slightly decreased, the percentages of CD4 and CD8 T cells in lymphocytes are similar, whereas B cell percentage increased in COVID-19 patients. T cells, especially CD8 T cells, showed an enhanced expression of late activation marker CD25 and exhaustion marker PD-1. Importantly, SARS-CoV-2 induced an increased percentage of T follicular helpher (Tfh)- and germinal center B-like (GCB-like) cells in the blood. However, the parameters in COVD-19 patients remained unchanged across various age groups. Therefore, we demonstrated that the T and B cells can be activated normally and exhibit functional features. These data provide a clue that the adaptive immunity in most people could be primed to induce a significant immune response against SARS-CoV-2 infection upon receiving standard medical care.

Natural Killer Cell Licensing Delineates NK “Helper/Repair” and NK “Effector/Suppressor” Subsets During Viral Infections

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 13-13
Author(s):  
Can M. Sungur ◽  
Anthony E. Zamora ◽  
Ethan G. Aguilar ◽  
Yajarayma Tang-Feldman ◽  
Juan Du ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Viral Infection ◽  
Nk Cells ◽  
Nk Cell ◽  
Cell Subset ◽  
Gm Csf ◽  
Cell Responses ◽  
Late Stages

Abstract Natural killer (NK) cells are innate lymphocytes with anti-viral and anti-tumor capabilities that can be divided into subsets based on differential receptor expression patterns. NK cells that express inhibitory receptors that can bind to the MHC class I molecules present in the host are considered to be “licensed,” fully functional NK cells with normal production of cytokines and cytotoxicity in response to targets. In contrast, “unlicensed” NK cells are unable to strongly bind to host MHC class I molecules and are in turn hyporesponsive to targets in terms of cytotoxicity and cytokine production. Recent data suggest that NK cells also regulate antigen-specific adaptive immune responses during the course of viral infection, playing a significant role in viral clearance and immunopathology. The specific populations of NK cells that may mediate these differential effects during the course of viral infection have not been identified. Here, we demonstrate differential effector and immunoregulatory functions of licensed versus unlicensed NK cells during influenza and murine cytomegalovirus (MCMV) infections in mouse models. We hypothesize that licensed NK cells serve a dual role as both effector and suppressor populations depending on the stage of viral infection. Similarly, unlicensed NK cells serve a dual role as helper and repair populations during the early and late stages of viral infection, respectively. We performed licensed and unlicensed NK cell subset depletions and then infected mice with influenza or MCMV and ascertained effects on: viral titers, antigen-specific T cell responses, and tissue pathology. Our data show that after influenza or MCMV infection, there is a significant reduction in antigen-specific CD4+ and CD8+ T cell populations in the presence of licensed NK cells as determined by tetramer-positive cells. Targeting of these T cells by the NK “effector/suppressor” licensed population appears later in the time course of infection and to be through NKG2D recognition and perforin-mediated lysis based on upregulation of NKG2D ligands Rae-1 and MULT1 on the T cells and the loss of T cell regulation with NKG2D blockade or perforin knockout mice. Depletion of the unlicensed NK “helper/repair” subset reduced the number of DCs in the lymph nodes and reduced total antigen-specific T cells. The unlicensed NK cells were found to home to the lymph node and produce increased levels of GM-CSF early during infection resulting in DC expansion. Additionally, the unlicensed NK cells are the primary producers of IL-22 based on intracellular staining in the damaged tissues in the late stages of viral infection, aiding in tissue regeneration. Adoptive transfer of unlicensed NK cells with IL-22 silencing through siRNA transfection into immunodeficient mice showed increased tissue damage and pathology as compared to transfer of non-IL-22 silenced NK cells. Collectively, these data suggest differential roles of licensed versus unlicensed NK cells that are both tissue and time-specific. At early stages of infection, licensed NK cells serve as direct anti-viral cells at the sites of infection while unlicensed cells promote DC expansion in the lymph nodes promoting antigen-specific T cell responses. Conversely, at the late stages of infection, licensed NK cells serve an immunoregulatory role by lysing antigen-specific T cells at the site of infection and in the lymph nodes, while unlicensed NK cells travel to the sites of injury to aid in tissue repair through production of IL-22. Importantly, a similar functional polarization of resting human NK cells was also observed after PMA/ionomycin stimulation, with a small population of unlicensed NK cells producing IL-22 and a bias towards GM-CSF secretion over IFNγ production by the unlicensed NK cell subset. We conclude that licensed NK cells have an effector/suppressor function while the unlicensed NK cells function as the helper/repair population suggesting distinct roles of NK cell subsets throughout the course of infection. By understanding the functions and characteristics of these NK cell populations, specific subsets can either by adoptively transferred or therapeutically targeted clinically to aid in different stages of immunological response including elimination of the virus, inhibiting the adaptive immune response, or aiding in tissue repair and regeneration. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Brain transforms natural killer cells that exacerbate brain edema after intracerebral hemorrhage

2020 ◽  
Vol 217 (12) ◽  
Author(s):  
Zhiguo Li ◽  
Minshu Li ◽  
Samuel X. Shi ◽  
Nan Yao ◽  
Xiaojing Cheng ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Nk Cells ◽  
Natural Killer ◽  
Brain Edema ◽  
Immune Cell ◽  
Nk Cell ◽  
Cell Subset ◽  
Cell Types ◽  
Chemokine Production ◽  
Perihematomal Edema

Perihematomal edema (PHE) occurs within hours after intracerebral hemorrhage (ICH), leading to secondary injury manifested by impaired blood–brain barrier (BBB) integrity and destruction of adjacent tissue. To dissect the mechanisms underlying PHE formation, we profiled human and mouse perihematomal tissues and identified natural killer (NK) cells as the predominant immune cell subset that outnumbers other infiltrating immune cell types during early stages of ICH. Unbiased clustering of single-cell transcriptional profiles revealed two major NK cell subsets that respectively possess high cytotoxicity or robust chemokine production features in the brain after ICH, distinguishing them from NK cells of the periphery. NK cells exacerbate BBB disruption and brain edema after ICH via cytotoxicity toward cerebral endothelial cells and recruitment of neutrophils that augment focal inflammation. Thus, brain-bound NK cells acquire new features that contribute to PHE formation and neurological deterioration following ICH.

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