scholarly journals NK Cells Help To Induce CD8+-T-Cell Immunity against Toxoplasma gondii in the Absence of CD4+ T Cells

2005 ◽  
Vol 73 (8) ◽  
pp. 4913-4921 ◽  
Author(s):  
Crescent L. Combe ◽  
Tyler J. Curiel ◽  
Magali M. Moretto ◽  
Imtiaz A. Khan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
Nk Cells ◽  
Cell Response ◽  
Nk Cell ◽  
Cell Activity ◽  
T Cell Immunity ◽  
Interleukin 12 ◽  
Cell Immunity

ABSTRACT CD8+ T-cell immunity plays an important role in protection against intracellular infections. Earlier studies have shown that CD4+ T-cell help was needed for launching in vivo CD8+ T-cell activity against these pathogens and tumors. However, recently CD4+ T-cell-independent CD8 responses during several microbial infections including those with Toxoplasma gondii have been described, although the mechanism is not understood. We now demonstrate that, in the absence of CD4+ T cells, T. gondii-infected mice exhibit an extended NK cell response, which is mediated by continued interleukin-12 (IL-12) secretion. This prolonged NK cell response is critical for priming parasite-specific CD8+ T-cell immunity. Depletion of NK cells inhibited the generation of CD8+ T-cell immunity in CD4−/− mice. Similarly neutralization of IL-12 reduces NK cell numbers in infected animals and leads to the down-regulation of CD8+ T-cell immunity against T. gondii. Adoptive transfer of NK cells into the IL-12-depleted animals restored their CD8+ T-cell immune response, and animals exhibited reduced mortality. NK cell gamma interferon was essential for cytotoxic T-lymphocyte priming. Our studies for the first time demonstrate that, in the absence of CD4+ T cells, NK cells can play an important role in induction of primary CD8+ T-cell immunity against an intracellular infection. These observations have therapeutic implications for immunocompromised individuals, including those with human immunodeficiency virus infection.

scholarly journals Lack of Interleukin-12 in p40-Deficient Mice Leads to Poor CD8+ T-Cell Immunity against Encephalitozoon cuniculi Infection

2010 ◽  
Vol 78 (6) ◽  
pp. 2505-2511 ◽  
Author(s):  
Magali M. Moretto ◽  
Elizabeth M. Lawlor ◽  
Imtiaz A. Khan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Scid Mice ◽  
T Cell Immunity ◽  
Interleukin 12 ◽  
Cell Immune Response ◽  
Encephalitozoon Cuniculi ◽  
Cell Immunity

ABSTRACT A CD8+ T-cell response is critical for protection against Encephalitozoon cuniculi infection. However, the factors responsible for the generation of CD8+ T-cell immunity during E. cuniculi infection and the cytokines involved in this process have not been identified. In the present study, we demonstrated that p40-deficient animals, which are unable to produce interleukin-12 (IL-12), have a serious defect in expansion of the CD8+ T-cell response which compromises the survival of an infected host. Adoptive transfer of CD8+ T cells from immunocompetent donors protected SCID mice infected with E. cuniculi, whereas administration of CD8+ T cells from p40−/− mice failed to protect infected SCID mice. In vitro dendritic cell (DC) cultures from knockout mice pulsed with E. cuniculi spores were unable to develop a robust CD8+ T-cell immune response. Addition of exogenous IL-12 or transfer of CD8+ T cells that were initially primed with DC from p40−/− animals to DC cultures from immunocompetent mice (directly or via transwells) led to optimal expansion of these cells. This IL-12-mediated reinstatement of CD8+ T-effector immunity was independent of gamma interferon (IFN-γ) as addition of antibody to the cultures failed to have an effect. These studies demonstrated that IL-12 plays a predominant role in the expansion of effector CD8+ T-cell immunity against E. cuniculi, which is critical for host survival. These findings are very important for understanding the protective immune mechanisms needed to protect an immunocompromised host against an opportunistic infection and can be extended to other microsporidial pathogens.

scholarly journals CD8+-T-Cell Immunity against Toxoplasma gondii Can Be Induced but Not Maintained in Mice Lacking Conventional CD4+ T Cells

2002 ◽  
Vol 70 (2) ◽  
pp. 434-443 ◽  
Author(s):  
Lori Casciotti ◽  
Kenneth H. Ely ◽  
Martha E. Williams ◽  
Imtiaz A. Khan
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
Cell Response ◽  
T Cell Response ◽  
T Cell Immunity ◽  
Cell Immune Response ◽  
Cell Immunity ◽  
Ifn Γ

ABSTRACT T-cell immunity is critical for survival of hosts infected with Toxoplasma gondii. Among the cells in the T-cell population, CD8+ T cells are considered the major effector cells against this parasite. It is believed that CD4+ T cells may be crucial for induction of the CD8+-T-cell response against T. gondii. In the present study, CD4−/− mice were used to evaluate the role of conventional CD4+ T cells in the immune response against T. gondii infection. CD4−/− mice infected with T. gondii exhibited lower gamma interferon (IFN-γ) messages in the majority of their tissues. As a result, mortality due to a hyperinflammatory response was prevented in these animals. Interestingly, T. gondii infection induced a normal antigen-specific CD8+-T-cell immune response in CD4−/− mice. No difference in generation of precursor cytotoxic T lymphocytes (pCTL) or in IFN-γ production by the CD8+-T-cell populations from the knockout and wild-type animals was observed. However, the mutant mice were not able to sustain CD8+-T-cell immunity. At 180 days after infection, the CD8+-T-cell response in the knockout mice was depressed, as determined by pCTL and IFN-γ assays. Loss of CD8+-T-cell immunity at this time was confirmed by adoptive transfer experiments. Purified CD8+ T cells from CD4−/− donors that had been immunized 180 days earlier failed to protect the recipient mice against a lethal infection. Our study demonstrated that although CD8+-T-cell immunity can be induced in the absence of conventional CD4+ T cells, it cannot be maintained without such cells.

scholarly journals Anti-tumor effects of RTX-240: an engineered red blood cell expressing 4-1BB ligand and interleukin-15

2021 ◽  
Author(s):  
Shannon L. McArdel ◽  
Anne-Sophie Dugast ◽  
Maegan E. Hoover ◽  
Arjun Bollampalli ◽  
Enping Hong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Blood Cell ◽  
Nk Cells ◽  
Red Blood Cell ◽  
Safety Profile ◽  
Nk Cell ◽  
Cell Activity ◽  
In Vivo Studies

AbstractRecombinant agonists that activate co-stimulatory and cytokine receptors have shown limited clinical anticancer utility, potentially due to narrow therapeutic windows, the need for coordinated activation of co-stimulatory and cytokine pathways and the failure of agonistic antibodies to recapitulate signaling by endogenous ligands. RTX-240 is a genetically engineered red blood cell expressing 4-1BBL and IL-15/IL-15Rα fusion (IL-15TP). RTX-240 is designed to potently and simultaneously stimulate the 4-1BB and IL-15 pathways, thereby activating and expanding T cells and NK cells, while potentially offering an improved safety profile through restricted biodistribution. We assessed the ability of RTX-240 to expand and activate T cells and NK cells and evaluated the in vivo efficacy, pharmacodynamics and tolerability using murine models. Treatment of PBMCs with RTX-240 induced T cell and NK cell activation and proliferation. In vivo studies using mRBC-240, a mouse surrogate for RTX-240, revealed biodistribution predominantly to the red pulp of the spleen, leading to CD8 + T cell and NK cell expansion. mRBC-240 was efficacious in a B16-F10 melanoma model and led to increased NK cell infiltration into the lungs. mRBC-240 significantly inhibited CT26 tumor growth, in association with an increase in tumor-infiltrating proliferating and cytotoxic CD8 + T cells. mRBC-240 was tolerated and showed no evidence of hepatic injury at the highest feasible dose, compared with a 4-1BB agonistic antibody. RTX-240 promotes T cell and NK cell activity in preclinical models and shows efficacy and an improved safety profile. Based on these data, RTX-240 is now being evaluated in a clinical trial.

scholarly journals Lack of CD4+ T Cells Does Not Affect Induction of CD8+ T-Cell Immunity against Encephalitozoon cuniculi Infection

2000 ◽  
Vol 68 (11) ◽  
pp. 6223-6232 ◽  
Author(s):  
Magali Moretto ◽  
Lori Casciotti ◽  
Brigit Durell ◽  
Imtiaz A. Khan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
T Cell Immunity ◽  
Cell Mediated Immunity ◽  
Wild Type ◽  
Encephalitozoon Cuniculi ◽  
Cell Immunity ◽  
Mouse Tissues

ABSTRACT Cell-mediated immunity has been reported to play an important role in defense against Encephalitozoon cuniculi infection. Previous studies from our laboratory have underlined the importance of cytotoxic CD8+ T lymphocytes (CTL) in survival of mice infected with E. cuniculi. In the present study, immune response against E. cuniculi infection in CD4+T-cell-deficient mice was evaluated. Similar to resistant wild-type animals, CD4−/− mice were able to resolve E. cuniculi infection even at a very high challenge dose (5 × 107 spores/mouse). Tissues from infected CD4−/− mice did not exhibit higher parasite loads in comparison to the parental wild-type mice. Conversely, at day 21 postinfection, susceptible CD8−/− mice had 1014 times more parasites in the liver compared to control wild-type mice. Induction of the CD8+ T-cell response in CD4−/− mice against E. cuniculi infection was studied. Interestingly, a normal antigen-specific CD8+T-cell response to E. cuniculi infection was observed in CD4−/− mice (precursor proliferation frequency, 1/2.5 × 104 versus 1/104 in wild-type controls). Lack of CD4+ T cells did not alter the magnitude of the antigen-specific CTL response (precursor CTL frequency; 1/1.4 × 104 in CD4−/− mice versus 1/3 × 104 in control mice). Adoptive transfer of immune CD8+ T cells from both CD4−/− and wild-type animals prevented the mortality in CD8−/− mice.E. cuniculi infection thus offers an example of an intracellular parasitic infection where CD8+ T-cell immunity can be induced in the absence of CD4+ T cells.

scholarly journals Children and adults with mild COVID-19 symptoms develop memory T cell immunity to SARS-CoV-2

2021 ◽  
Author(s):  
Patricia Kaaijk ◽  
Veronica Olivo Pimentel ◽  
Maarten E. Emmelot ◽  
Martien Poelen ◽  
Alper Cevirgel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
T Cell Immunity ◽  
Immune Memory ◽  
Effector Memory ◽  
Longitudinal Assessment ◽  
Memory T Cell ◽  
Cell Immunity

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to considerable morbidity/mortality worldwide, but most infections, especially among children, have a mild course. However, it remains largely unknown whether infected children develop cellular immune memory. Methods: To determine whether a memory T cell response is being developed as an indicator for long-term immune protection, we performed a longitudinal assessment of the SARS-CoV-2-specific T cell response by IFN-γ ELISPOT and activation marker expression analyses of peripheral blood samples from children and adults with mild-to-moderate COVID-19. Results: Upon stimulation of PBMCs with heat-inactivated SARS-CoV-2 or overlapping peptides of spike (S-SARS-CoV-2) and nucleocapsid proteins, we found S-SARS-CoV-2-specific IFN-ɣ T cell responses in most infected children (83%) and all adults (100%) that were absent in unexposed controls. Frequencies of SARS-CoV-2-specific T cells were higher in infected adults, especially in those with moderate symptoms, compared to infected children. The S-SARS-CoV-2 IFN-ɣ T cell response correlated with S1-SARS-CoV-2-specific serum IgM, IgG, and IgA antibody concentrations. Predominantly, effector memory CD4+ T cells of a Th1 phenotype were activated upon exposure to SARS-CoV-2 antigens, which persisted for 4-8 weeks after symptom onset. We detected very low frequencies of SARS-CoV-2-reactive CD8+ T cells in these individuals. Conclusions: Our data indicate that an antigen-specific memory CD4+ T cell response is induced in children and adults with mild SARS-CoV-2 infection. T cell immunity induced after mild COVID-19 could contribute to protection against re-infection.

scholarly journals Assessment of T-cell immunity to SARS-CoV-2 in COVID-19 convalescents and vaccinated subjects, using TigraTest® SARS-CoV-2 ELISPOT kit

2021 ◽  
Vol 21 (3) ◽  
pp. 178-192
Author(s):  
D. A. Poteryaev ◽  
S. G. Abbasova ◽  
P. E. Ignatyeva ◽  
O. M. Strizhakova ◽  
S. V. Kolesnik ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Cell Response ◽  
Human Peripheral Blood ◽  
T Cell Response ◽  
T Cell Immunity ◽  
Cell Immunity

With the onset of the COVID-19 pandemic, a number of molecular-based tests have been developed to diagnose SARS-CoV-2 infection. However, numerous available serological tests lack sufficient sensitivity or specificity. They do not detect specific antibodies in a significant proportion of patients with PCR-confirmed COVID-19. There is evidence that some convalescents have a relatively short-lived humoral immunity. In contrast, a number of publications have shown that T-cell response to human coronaviruses, including SARS-CoV-1, MERS, and SARS-CoV-2, can be strong and long-term. Assessment of T-cell immunity to SARS-CoV-2 is important not only for stratification of risks and identification of potentially protected populations with immunity acquired as a result of previous infection, but also for determining immunogenicity and potential efficacy of vaccines under development. The existing methods of quantitative or semi-quantitative assessment of specific T-cell response are mainly used in scientific research and are not standardised. The aim of the study was to develop and verify experimentally a test kit to be used in a standardised procedure for in vitro determination of T-cells specific to SARS-CoV-2 antigens, in human peripheral blood. Materials and methods: the TigraTest® SARS-CoV-2 kit developed by GENERIUM, which determines the number of T-cells secreting interferon gamma in vitro, was tested in the study. Samples of venous blood of volunteers from three different groups were analysed in the study: presumably healthy volunteers; COVID-19 convalescents; individuals vaccinated against SARS-CoV-2. Results: the authors developed the TigraTest® SARS-CoV-2 kit for in vitro determination of T-cells specific to SARS-CoV-2 antigens in human peripheral blood, demonstrated its specificity and performed preliminary assessment of its sensitivity. The study analysed the range and magnitude of the T-cell response in convalescent and vaccinated individuals. A pronounced T-cell response was also shown in some individuals with no symptoms or with unconfirmed diagnosis. It was discovered that the mean T-cell response to peptides of the spike protein (S-protein) was higher in the vaccinated individuals than in the convalescent patients. A correlation was determined between the severity of the disease and the level of T-cell response. Specific contributions of various groups of antigens to the T-cell response after COVID-19 infection were also determined. Conclusions: the TigraTest® SARS-CoV-2 kit is a specific and sensitive tool for the assessment of T-cell immunity to the SARS-CoV-2 virus, which can also be used for vaccinated individuals. The kit may be used in clinical practice for comprehensive assessment of immunity to SARS-CoV-2.

scholarly journals NK cells negatively regulate CD8 T cells to promote immune exhaustion and chronic Toxoplasma gondii infection

2019 ◽  
Author(s):  
Daria L. Ivanova ◽  
Ryan Krempels ◽  
Stephen L. Denton ◽  
Kevin D. Fettel ◽  
Giandor M. Saltz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
Nk Cells ◽  
Cell Population ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Chronic Phase ◽  
Cd8 T Cell ◽  
Cell Compartment

AbstractNK cells regulate CD4+ and CD8+ T cells in acute viral infection, vaccination and the tumor microenvironment. NK cells also become exhausted in chronic activation settings. The mechanisms causing these ILC responses and their impact on adaptive immunity are unclear. CD8+ T cell exhaustion develops during chronic Toxoplasma gondii (T. gondii) infection resulting in parasite reactivation and death. How chronic T. gondii infection impacts the NK cell compartment is not known. We demonstrate that NK cells do not exhibit hallmarks of exhaustion. Their numbers are stable and they do not express high PD1 or LAG3. NK cell depletion with anti-NK1.1 is therapeutic and rescues chronic T. gondii infected mice from CD8+ T cell exhaustion dependent death, increases survival after lethal secondary challenge and reduces parasite reactivation. Anti-NK1.1 treatment increased polyfunctional CD8+ T cell responses in spleen and brain and reduced CD8+ T cell apoptosis. Chronic T. gondii infection promotes the development of a modified NK cell compartment, which does not exhibit normal NK cell behavior. This splenic CD49a-CD49b+NKp46+ NK cell population develops during the early chronic phase of infection and increases through the late chronic phase of infection. They are Ly49 and TRAIL negative and are enriched for expression of CD94/NKG2A and KLRG1. They do not produce IFNγ, are IL-10 negative, do not increase PDL1 expression, but do increase CD107a on their surface. They are also absent from brain. Based on the NK cell receptor phenotype we observed NKp46 and CD94-NKG2A cognate ligands were measured. Activating NKp46 (NCR1-ligand) ligand increased and NKG2A ligand Qa-1b expression was reduced. Blockade of NKp46 also rescued the chronically infected mice from death. Immunization with a single dose non-persistent 100% protective T. gondii vaccination did not induce this cell population in the spleen, suggesting persistent infection is essential for their development. We hypothesize chronic T. gondii infection induces an NKp46 dependent modified NK cell population that reduces functional CD8+ T cells to promote persistent parasite infection in the brain. NK cell targeted therapies could enhance immunity in people with chronic infections, chronic inflammation and cancer.

Cytotoxic cells induced during lymphocytic choriomeningitis virus infection of mice: natural killer cell activity in cultured spleen leukocytes concomitant with T-cell-dependent immune interferon production

1980 ◽  
Vol 30 (2) ◽  
pp. 473-483
Author(s):  
R M Welsh ◽  
W F Doe
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Nk Cell ◽  
Cytotoxic T Cells ◽  
Cell Activity ◽  
Lymphocytic Choriomeningitis ◽  
Type I ◽  
Spleen Cells

The characteristics and specificities of spleen and peritoneal cytotoxic cells generated during lymphocytic choriomeningitis virus (LCMV) infection of C3H/St mice were examined. Activated natural killer (NK) cell activity was identified in fresh leukocyte populations from the 2nd to 8th days postinfection, whereas virus-specific cytotoxic T-cell activity was detected from the 6th to 14th days. When leukocytes were cultured overnight at 37 degrees C before assay, T-cell activity was still observed, but nonspecific activated NK cell-like cytotoxicity was only detected on the 6th and to a lesser degree the 8th day postinfection. Overnight culture of leukocytes taken earlier in the infection eliminated their NK cell activity. Similar activities were seen with spleen cell, plastic-adherent peritoneal cell, and nonadherent peritoneal cell populations. The virus-specific cytotoxicity observed with adherent peritoneal cells was due to contamination with cytotoxic T cells, as shown by H-2-restricted cytotoxicity and sensitivity to anti-theta antibody and complement. The nonspecific cultured day 6 effector cell from either the spleen or peritoneum displayed killing specificities and other physical properties identical to those of activated NK cells, but had sensitivities to anti-theta antibody and complement intermediate between activated day 3 NK cells and cytotoxic T cells. Culture stable NK-like cells were not found in athymic nude mice, suggesting a T-cell-dependent mechanism. Whereas LCMV spleen homogenates contained 10-fold-higher levels of interferon at day 2 than at day 6 postinfection, substantially more (nearly 20-fold) interferon was made in cultures of day 6 cells than day 2 cells. Spleen interferon was predominantly type I, whereas the culture interferon was predominantly type II, as shown by acid lability studies. Significant levels of interferon were produced by nylon-wool-passed day 6 spleen cells, and virtually all interferon production was eliminated by treatment of either day 2 or day 6 cells with antibody to theta antigen and complement, suggesting that T cells produced the interferon in vitro. Furthermore, athymic nude mice had no culture-stable NK cells 6 days postinfection, and spleen cells from them failed to produce significant levels of interferon in vitro. Addition of interferon (type I, fibroblast) to cultured C3H spleen cells affect the already elevated levels of cytotoxicity in day 6 cultures, suggesting that the NK cells in the day 6 culture were already activated. Our results suggest that T cells responding to LCMV infection secrete interferon type II which causes the continued activation of NK cells in culture. The resulting population of activated NK cells therefore appears to be relatively stable in culture and to express more theta antigen because of this T-cell dependence. Although one could mistakenly or allospecific cytotoxic T cells or cytotoxic macrophages, more careful examination shows that they are most likely activated NK cells...

scholarly journals A DNA-based cancer vaccine enhances lymphocyte cross talk by engaging the NKG2D receptor

Blood ◽  
2006 ◽  
Vol 107 (8) ◽  
pp. 3251-3257 ◽  
Author(s):  
He Zhou ◽  
Yunping Luo ◽  
Charles D. Kaplan ◽  
Jörg A. Krüger ◽  
Sung-Hyung Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Dna Vaccine ◽  
Cross Talk ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Cell Activity ◽  
Nk Cell Activity ◽  
Nkg2d Receptor

Abstract The NKG2D receptor is a stimulatory receptor expressed on NK cells and activated CD8 T cells. We previously demonstrated that engaging the NKG2D receptor markedly improved the efficacy of a survivin-based DNA vaccine. The combination vaccine, encoding both the NKG2D ligand H60 and survivin, activates innate and adaptive antitumor immunity and results in better protection against tumors of different origin and NKG2D expression levels. Here we demonstrate that the enhanced vaccine efficacy is in part attributable to increased cross talk between lymphocytes. Depletion of CD8 T cells during priming reduces the vaccine-induced activation of dendritic cells (DCs) and NK cell activity. Depletion of NK cells during priming leads to reduced DC activation and CTL activity. However, depletion of CD4 T cells results in the activation of DCs, NK cells, and CD8 T cells and enhances NK cell activity. The pH60/Survivin vaccine also increases DCs and NK cells but decreases CD4 T cell homing to Peyer patches, presumably as a result of changes in the homing receptor profile. Thus, by preferentially activating and attracting positive regulators and reducing negative regulators in Peyer patches, this dual-function DNA vaccine induces a microenvironment more suitable for NK cell activation and T cell priming.

scholarly journals Mucosal Vaccination Primes NK Cell-Dependent Development of CD8+ T Cells Against Pulmonary Brucella Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Ella Bhagyaraj ◽  
Hongbin Wang ◽  
Xinghong Yang ◽  
Carol Hoffman ◽  
Ali Akgul ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Cell Response ◽  
Nk Cell ◽  
T Cell Response ◽  
Innate Immune ◽  
Cell Depletion ◽  
Ifn Γ ◽  
And Migration

Past studies with the live, double-mutant B. abortus (znBAZ) strain resulted in nearly complete protection of mice against pulmonary challenge with wild-type (wt) Brucella via a dominant CD8+ T cell response. To understand the contribution innate immune cells in priming CD8+ T cell responses, mice were nasally dosed with wt B. abortus, smooth vaccine strain 19 (S19), or znBAZ, and examined for innate immune cell activation. Flow cytometric analysis revealed that znBAZ, but not wt B. abortus nor S19 infection, induces up to a 5-fold increase in the frequency of IFN-γ-producing NK cells in mouse lungs. These NK cells express increased CXCR3 and Ki67, indicating their recruitment and proliferation subsequent to znBAZ infection. Their activation status was augmented noted by the increased NKp46 and granzyme B, but decreased NKG2A expression. Further analysis demonstrated that both lung caspase-1+ inflammatory monocytes and monocyte-derived macrophages secrete chemokines and cytokines responsible for NK cell recruitment and activation. Moreover, neutralizing IL-18, an NK cell-activating cytokine, reduced the znBAZ-induced early NK cell response. NK cell depletion also significantly impaired lung dendritic cell (DC) activation and migration to the lower respiratory lymph nodes (LRLNs). Both lung DC activation and migration to LRLNs were significantly impaired in NK cell-depleted or IFN-γ-/- mice, particularly the CD11b+ and monocytic DC subsets. Furthermore, znBAZ vaccination significantly induced CD8+ T cells, and upon in vivo NK cell depletion, CD8+ T cells were reduced 3-fold compared to isotype-treated mice. In summary, these data show that znBAZ induces lung IFN-γ+ NK cells, which plays a critical role in influencing lung DC activation, migration, and promoting protective CD8+ T cell development.

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