Differential expression of maturation and activation markers on NK cells in patients with active and latent tuberculosis

2021 ◽  
Author(s):  
Nurhan Albayrak ◽  
Violette Dirix ◽  
Laetitia Aerts ◽  
Anne Van Praet ◽  
Audrey Godefroid ◽  
...  
Keyword(s):  
Nk Cells ◽  
Differential Expression ◽  
Latent Tuberculosis ◽  
Activation Markers

scholarly journals CRISPR-Targeted CAR Gene Insertion Using Cas9/RNP and AAV6 Enhances Anti-AML Activity of Primary NK Cells

2021 ◽  
Author(s):  
Meisam Naeimi Kararoudi ◽  
Shibi Likhite ◽  
Ezgi Elmas ◽  
Kenta Yamamoto ◽  
Maura Schwartz ◽  
...  
Keyword(s):  
Nk Cells ◽  
Efficient Method ◽  
Myeloid Leukemia ◽  
Human Peripheral Blood ◽  
Transduction Efficiency ◽  
Proof Of Concept ◽  
Activation Markers ◽  
Adeno Associated Virus ◽  
Gene Insertion ◽  
Signaling Domains

Human peripheral blood natural killer (NK) cells have intense antitumor activity and have been used successfully in several clinical trials. Modifying NK cells with a chimeric antigen receptor (CAR) can improve their targeting and increase specificity. Recently, we described an efficient method for gene targeting in NK cells using Cas9/ribonucleoprotein (RNP) complexes. Here we combined this approach with single stranded (ss) or self-complementary (sc) Adeno-associated virus (AAV)-mediated gene delivery for gene insertion into a safe-harbor locus using a wide variety of homology arms for homology repair (HR) and non-homologous directed CRISPR-assisted insertion tagging (CRISPaint) approaches. For proof-of-concept, we generated mCherry-expressing primary NK cells and determined that sc vectors with 300bp homology 30 arms had optimal transduction efficiency. Then, we generated CD33-targeting CAR NK cells with differing transmembrane and signaling domains (CD4/4-1BB+CD3ζ and NKG2D/2B4+CD3ζ) and expanded them on CSTX002 feeder cells. Expansion kinetics were unaltered and the expanded NK cells maintained high CAR expression (mean 68% CAR+). The CD33-CAR-NK cells showed increased activation markers and enhanced antileukemic activity with improved killing kinetics against CD33-positive acute myeloid leukemia (AML) cell lines and primary samples. Using targeted sequencing we demonstrated the accuracy of CAR gene insertion in human primary NK cells genome. Site-directed insertion using RNP and scAAV6 is an efficient method for stable genetic transfer into primary NK cells that has broad potential for fundamental discovery and therapeutic applications.

scholarly journals IL-7 expands lymphocyte populations and enhances immune responses to sipuleucel-T in patients with metastatic castration-resistant prostate cancer (mCRPC)

2021 ◽  
Vol 9 (8) ◽  
pp. e002903
Author(s):  
Russell K Pachynski ◽  
Chihiro Morishima ◽  
Russell Szmulewitz ◽  
Lauren Harshman ◽  
Leonard Appleman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Immune Responses ◽  
Nk Cells ◽  
Observation Group ◽  
Castration Resistant Prostate Cancer ◽  
Activation Markers ◽  
Castration Resistant ◽  
Ifn Γ ◽  
Over Time

BackgroundSipuleucel-T (sip-T) is a Food and Drug Administration (FDA)-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). We hypothesized that combining sip-T with interleukin (IL)-7, a homeostatic cytokine that enhances both B and T cell development and proliferation, would augment and prolong antigen-specific immune responses against both PA2024 (the immunogen for sip-T) and prostatic acid phosphatase (PAP).MethodsFifty-four patients with mCRPC treated with sip-T were subsequently enrolled and randomized 1:1 into observation (n=26) or IL-7 (n=28) arms of a phase II clinical trial (NCT01881867). Recombinant human (rh) IL-7 (CYT107) was given weekly×4. Immune responses were evaluated using flow cytometry, mass cytometry (CyTOF), interferon (IFN)-γ ELISpot, 3H-thymidine incorporation, and ELISA.ResultsTreatment with rhIL-7 was well tolerated. For the rhIL-7-treated, but not observation group, statistically significant lymphocyte subset expansion was found, with 2.3–2.6-fold increases in CD4+T, CD8+T, and CD56bright NK cells at week 6 compared with baseline. No significant differences in PA2024 or PAP-specific T cell responses measured by IFN-γ ELISpot assay were found between rhIL-7 and observation groups. However, antigen-specific T cell proliferative responses and humoral IgG and IgG/IgM responses significantly increased over time in the rhIL-7-treated group only. CyTOF analyses revealed pleiotropic effects of rhIL-7 on lymphocyte subsets, including increases in CD137 and intracellular IL-2 and IFN-γ expression. While not powered to detect clinical outcomes, we found that 31% of patients in the rhIL-7 group had prostate specific antigen (PSA) doubling times of >6 months, compared with 14% in the observation group.ConclusionsTreatment with rhIL-7 led to a significant expansion of CD4+ and CD8+ T cells, and CD56bright natural killer (NK) cells compared with observation after treatment with sip-T. The rhIL-7 treatment also led to improved antigen-specific humoral and T cell proliferative responses over time as well as to increased expression of activation markers and beneficial cytokines. This is the first study to evaluate the use of rhIL-7 after sip-T in patients with mCRPC and demonstrates encouraging results for combination approaches to augment beneficial immune responses.

Lenalidomide Strongly Enhances Natural Killer (NK) Cell Mediated Antibody-Dependent Cellular Cytotoxicity (ADCC) of Rituximab Treated Non-Hodkin’s Lymphoma Cell Lines In Vitro.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3714-3714 ◽  
Author(s):  
Lei Wu ◽  
Peter Schafer ◽  
George Muller ◽  
David Stirling ◽  
J. Blake Bartlett
Keyword(s):  
Nk Cells ◽  
Tumor Cells ◽  
Cell Lines ◽  
Nk Cell ◽  
Dependent Manner ◽  
Activation Markers ◽  
Early Results ◽  
Ifn Γ ◽  
Dose Dependent

Abstract Lenalidomide (Revlimid® is approved for the treatment of transfusion-dependent patients with anemia due to low- or intermediate-1-risk MDS associated with a del 5q cytogenetic abnormality with or without additional cytogenetic abnormalities, and in combination with dexamethasone is for the treatment of multiple myeloma patients who have received at least one prior therapy. Encouraging early results suggest a potential for clinical efficacy in B cell non-Hodgkin’s lymphoma (NHL). Potential mechanisms of action include anti-angiogenic, anti-proliferative and immunomodulatory activities. Lenalidomide has been shown to enhance Th1-type cytokines and T cell and NK cell activation markers in patients with advanced cancers. Furthermore, lenalidomide has been shown to enhance rituximab-mediated protection in a SCID mouse lymphoma model in vivo. We have utilized an in vitro ADCC system to assess the ability of lenalidomide to directly enhance human NK cell function in response to therapeutic antibodies, such as rituximab (chimeric anti-CD20 mAb). Isolated NK cells produced little or no IFN-γ in response to IgG and/or IL-2 or IL-12. However, pre-treatment of NK cells with lenalidomide greatly enhanced IFN-γ production by NK cells in a dose-dependent manner. In a functional ADCC assay, NHL cell lines (Namalwa, Farage & Raji) were pre-coated with rituximab and exposed to NK cells pre-treated with lenalidomide in the presence of either exogenous IL-2 or IL-12. After 4 hours in culture the viability of the tumor cells was assessed. Lenalidomide consistently and synergistically increased the killing of tumor cells in a dose-dependent manner and up to >4-fold compared to rituximab alone. Rituximab alone had only a small effect in this model and there was no killing of cells in the absence of rituximab. The presence of either exogenous IL-2 or IL-12 was required to see enhanced killing by lenalidomide. In cancer patients lenalidomide has been shown to increase serum IL-12 levels and is also known to induce IL-2 production by T cells in vitro. Potential mechanisms for enhanced ADCC include increased signaling through NK FCγ receptors and/or IL-2 or IL-12 receptors. However, we found that these receptors are unaffected by lenalidomide, although downstream effects on NK signaling pathways are likely and are being actively investigated. In conclusion, we have shown that lenalidomide strongly enhances the ability of rituximab to induce ADCC mediated killing of NHL cells in vitro. This provides a strong rationale for combination of these drugs in patients with NHL and CLL.

Immunostimulatory Properties of the Human Ortholog of the GMCSF/IL2 Fusion Protein for Cell Based Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4894-4894
Author(s):  
Claudia Penafuerte Graduate ◽  
Jacques Galipeau
Keyword(s):  
Fusion Protein ◽  
Nk Cells ◽  
Cell Expansion ◽  
Cell Activation ◽  
Nk Cell ◽  
Ex Vivo ◽  
Potential Candidate ◽  
Activation Markers ◽  
Cell Based Therapy

Abstract NK cells constitute a potential candidate for cancer cell therapy because they express a diverse array of inhibitory and activating receptors, which recognize and kill infected or tumor cells without prior immune sensitization. However, autologous NK cell mediated adoptive immunotherapy is restricted due to insufficient cytolytic activity of NK cells from patient with aggressive malignancies. In contrast, the infusion of alloreactive NK cells has shown more successful outcomes in the treatment of cancer, but this approach also presents difficulties such as the high doses of cytokines required to induce NK cell expansion ex vivo, which may also sensitize NK cells to apoptosis. Therefore, a critical issue for NK cell based therapy is the use of appropriate growth factors or cytokines that promote NK cell expansion and activation. We have previously shown that a murine GM-CSF/IL-2 fusion protein (aka GIFT2) displays novel antitumor properties in vivo compared to both cytokines in combination regarding tumor site recruitment of macrophages and significant functional NK cell infiltration [Stagg et al., Cancer Research (December 2004)]. In the present work, we found that human GIFT2 will lead to a substantial two fold proliferation of human blood-derived NK cells which is significantly (p<0.05) superior to either IL2 or GMCSF single cytokine treatment or both cytokines combined at equimolar concentration. In addition, we observed that GIFT2 leads to robust expression of NK-cell activation markers CD69 and CD107a. In conclusion, the human GIFT2 fusokine is a novel and potent tool for ex vivo expansion of activated NK cells which may be of use in cell-based immunotherapy of cancer.

High-Throughput Screening by Flow Cytometry Identifies Reduced Expression of CD48 As a Universal Characteristic of T-ALL and a Suitable Target for Minimal Residual Disease (MRD) Detection

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2547-2547 ◽  
Author(s):  
Brent L. Wood ◽  
Greg Levin ◽  
Megan Wilson ◽  
Stuart S. Winter ◽  
Kimberly Dunsmore ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Differential Expression ◽  
Fluorescence Intensity ◽  
Pediatric Patients ◽  
Nk Cell ◽  
Residual Disease ◽  
Median Fluorescence Intensity ◽  
Flow Cytometric

Abstract Abstract 2547 The flow cytometric detection of minimal residual disease (MRD) relies on the differential expression of antigens between normal and leukemic cell populations of similar lineage. In T-cell lymphoblastic leukemia (T-ALL), the principal normal populations from which leukemic blasts must be distinguished are mature T cells and NK cells, as immature T cells are not normally present in peripheral blood or bone marrow. Current methods rely on a relatively small number of antigens, some of which are not stable following therapy. In particular, immature antigens such as TdT and CD99 that distinguish leukemic and mature cells at diagnosis often revert to mature levels after therapy. The subset of T-ALL cases having expression of surface CD3 can be particularly problematic. Consequently, the identification of novel antigens to supplement those currently in use is highly desirable. We undertook a systematic search for novel antigens capable of distinguishing T-ALL from mature T cell and NK cell populations using a high-throughput flow cytometric screening technique. LyoPlates (Becton-Dickinson) containing antibodies against 242 unique antigenic specificities in a 96 well plate format were used to assay mononuclear cells obtained from 3 normal peripheral blood donors and 9 pediatric patients with T-ALL. The T-ALL cases covered the range of immunophenotypes seen in this disorder. The 9-color assay (1 detection and 8 gating fluorochromes) was performed on an LSRII and was capable of identifying discrete T cell, NK cell and Blast cell subpopulations. Comparison of the median fluorescence intensity of each of the 242 unique antigens identified CD48 as one of the few antigens that showed consistent differential expression between mature T cells and NK cells in comparison to leukemic blasts from T-ALL. To determine whether differential expression of CD48 represents a universal characteristic of the disorder, we assayed 126 consecutive pretreatment T-ALL samples from pediatric patients enrolled on Children's Oncology Group protocol AALL0434. An 8 color flow cytometric assay was employed using the following antibody combination: CD48 FITC, CD5 PE, CD16+CD56 PE-Cy5, CD3 PE-Cy7, CD8 V450 or BV421, CD4 A594, CD7 APC, CD45 APC-Cy7. Comparison of the median fluorescence intensity of CD48 between leukemic blasts and normal T and NK cells within the same specimen revealed consistently decreased expression of CD48 on leukemic blasts (see Figure 1) with some variation in intensity. This finding was highly statistically significant (p<4E-105). The stability of CD48 expression following therapy was determined by assay of CD48 expression in 126 bone marrow samples obtained at day 29 following induction chemotherapy, representing paired samples from the patients whose pretreatment samples were assayed above. The same 8 color reagent combination was used in conjunction with the standard MRD assayed utilized for the treatment protocol, a two-tube 9 color assay. Of these samples, 50 (39.7%) showed detectable MRD using the standard assay. At end induction, the ratio of CD48 median fluorescence intensity between the leukemic MRD population and normal T and NK cells within the same sample remained abnormal in most cases. It was unchanged in 26% of cases, decreased (i.e. became more aberrant) in 24%, and increased in 50%, but in most of the latter cases remained significantly <1. However, in 5 cases (10%), CD48 increased to the level seen on normal mature T and NK cells. The changes following therapy were due largely to changes in the expression of CD48 on leukemic blasts as the level of expression of normal T and NK cells was more stable. No association between apparent immunophenotypic maturational stage or surface CD3 expression was identified. We conclude that the expression of CD48 is consistently reduced on leukemic blasts from patients with pediatric T-ALL in comparison to normal mature T and NK cells at the time of diagnosis. Following therapy, the expression of CD48 undergoes modulation, but remains different from mature T and NK cells in 90% of patients. This suggests that CD48 is a useful addition to reagent combinations for the purpose of MRD assessment in pediatric T-ALL. Disclosures: Wood: BD Biosciences: Research Funding. Borowitz:BD Biosciences: Research Funding.

Influence of Lenalidomide Treatment on Immune Effector Cells From High-Risk Smoldering Multiple Myeloma (SMM) Patients,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3944-3944
Author(s):  
Bruno Paiva ◽  
Maria Victoria Mateos ◽  
Lucía López-Corral ◽  
María-Belén Vidriales ◽  
Miguel T. Hernandez ◽  
...  
Keyword(s):  
T Cells ◽  
High Risk ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Γδ T Cells ◽  
Activation Markers ◽  
Hla Dr ◽  
Activation Profile ◽  
Immunomodulatory Properties

Abstract Abstract 3944 Lenalidomide is an immunomodulatory agent that enhances T and NK cell activation, being this consideration as a major player in its anti-myeloma effect. However, in MM lenalidomide is usually combined with the immunosuppressant dexamethasone, which has raised questions regarding a potential abrogation of this immunomodulatory effect. In fact, this may be a dilemma upon treating early stage MM patients with lenalidomide +/− dexamethasone. Moreover, our current knowledge of the immune system in SMM is limited. Herein we evaluated by multiparameter flow cytometry (MFC) immunophenotyping peripheral blood (PB) T and NK cells from high-risk SMM patients (N=33), treated according to the QUIREDEX trial (NCT 00480363): an induction phase of 9 four-week cycles of LenDex followed by maintenance with lenalidomide until disease progression. To evaluate the immune status of T and NK cells of SMM patients, we compared them at baseline vs healthy adults (HA) aged over 60 years (N=10). To assess the effect of LenDex on T and NK cells of SMM patients, we compared baseline samples vs those studied after 3 and 9 cycles of LenDex. To address the question whether dexamethasone antagonizes the immunomodulatory properties of lenalidomide, we compared in 11 of the 33 patients, the PB T and NK cells at the end of induction (9th cycle of LenDex) vs during maintenance (lenalidomide alone and at least 3 months after dexamethasone discontinuation). The percentage of PB T cells in high-risk SMM patients at baseline was increased when compared to HA (23% vs 17%; P=.02), mainly due to expansion of CD8 T cells (P=.03). Of note, γδ T cells were also increased in SMM (0.8% vs 0.3%; P=.003). In turn, no differences (P>.05) were noted for both the CD56dim and CD56bright NK cell compartments. However, when a more detailed immunophenotypic characterization was carried out, CD4 and/or CD8 T cells from SMM patients showed decreased expression of activation markers (CD25, P≤.04; CD54, P<.001 and CD154, P=.002), as well as decreased production of the Th1 related cytokines (IFNγ, P=.03; TNFα, P≤.003; and IL-2, P=.02). We then investigated the effect of LenDex treatment. After 3 and 9 cycles of LenDex both CD4 and/or CD8 T cells showed up-regulation of Th1related chemokines (CCR5; p<.001) and cytokine production (IFNγ, P=.03; TNFα, P=.03 and IL-2, P=.02), as well as increased expression of activation markers (CD69, P≤.005; CD25, P<.001; CD28, P≤.04; CD54, P<.001 and HLA-DR, P<.001). Similarly, CD56dim and CD56bright NK cells showed up-regulation of HLA-DR (P<.001), the antibody-dependent cell-mediated cytotoxicity associated receptor CD16 (p≤.005), and the adhesion molecules CD11a (p≤.001) and CD11b (p≤.005). Concerning cell cycle analysis, the percentage of cells in S-phase was significantly increased from baseline vs. 3 vs. 9 cycles of LenDex for T CD4 (0.04% vs 0.13% vs 0.13%; p<.001), CD8 (0.05% vs 0.13% vs 0.18%; p<.001) and NK cells (0.07% vs 0.16% vs 0.15%; p<.001). Interestingly, an unsupervised cluster analysis of the overall immunophenotypic expression profile obtained after 9 cycles of LenDex was able to discriminate two groups of patients with different activation profiles particularly on T CD8 cells, with differences (P<.05) in both their percentage in PB and expression of activation, Th1 and maturation markers. Patients displaying a higher activation profile showed a trend towards increased depth of response after 9 cycles of LenDex (sCR+CR: 31% vs 15%; p=.229), as well as time-to progression (TTP) to symptomatic MM (TTP at 2-years: 100% vs 79%; P=.177). Finally, we explored whether the immunomodulatory properties of lenalidomide could be increased when dexamethasone was removed for the maintenance phase. Regarding T and NK cell distribution, only an increase in the percentage of CD4 T cells was found (9% vs. 12%, P=.04), whereas no differences (P>.05) were noted regarding the immunophenotypic expression profile of T and NK cells studied. In summary, we show that in high-risk SMM patients at baseline CD8 and γδ T cells are increased but overall T cells show an impaired activation profile. Treatment with LenDex induces an activation and proliferation of T and NK cells which may contribute to disease control. Finally, our results do not show an inhibition of the immunomodulatory effects of lenalidomide by the concomitant use of dexamethasone. Disclosures: Paiva: Celgene: Honoraria; Janssen: Honoraria. Off Label Use: lenalidomide is not approved for smoldering myeloma. Mateos:Janssen: Honoraria; Celgene: Honoraria. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria.

scholarly journals Circulating and Tumor-Infiltrating NK Cells From Clear Cell Renal Cell Carcinoma Patients Exhibit a Predominantly Inhibitory Phenotype Characterized by Overexpression of CD85j, CD45, CD48 and PD-1

2021 ◽  
Vol 12 ◽  
Author(s):  
Andrea Ziblat ◽  
Ximena Lucía Raffo Iraolagoitia ◽  
Sol Yanel Nuñez ◽  
Nicolás Ignacio Torres ◽  
Florencia Secchiari ◽  
...  
Keyword(s):  
Nk Cells ◽  
Renal Cell ◽  
Clear Cell ◽  
Nk Cell ◽  
The Cancer Genome Atlas ◽  
Phenotypic Analysis ◽  
Cell Renal Cell Carcinoma ◽  
Activation Markers ◽  
Mhc I ◽  
Phenotype Analysis

Although natural killer (NK) cells infiltrate clear cell renal cell carcinomas (ccRCC), the most frequent malignancy of the kidney, tumor progression suggests that they become dysfunctional. As ccRCC-driven subversion of NK cell effector functions is usually accompanied by phenotypic changes, analysis of such alterations might lead to the identification of novel biomarkers and/or targets in immuno-oncology. Consequently, we performed a phenotypic analysis of peripheral blood NK cells (PBNK) and tumor-infiltrating NK cells (TINK) from ccRCC patients. Compared to HD, PBNK from ccRCC patients exhibited features of activated cells as shown by CD25, CD69 and CD62L expression. They also displayed increased expression of DNAM-1, CD48, CD45, MHC-I, reduced expression of NKG2D, and higher frequencies of CD85j+ and PD-1+ cells. In addition, compared to PBNK from ccRCC patients, TINK exhibited higher expression of activation markers, tissue residency features and decreased expression of the activating receptors DNAM-1, NKp30, NKp46, NKp80 and CD16, suggesting a more inhibitory phenotype. Analysis of The Cancer Genome Atlas (TCGA) revealed that CD48, CD45, CD85j and PD-1 are significantly overexpressed in ccRCC and that their expression is associated with an NK cell infiltration signature. Calculation of z-scores revealed that their expression on PBNK, alone or combined, distinguished ccRCC patients from HD. Therefore, these molecules emerge as novel potential biomarkers and our results suggest that they might constitute possible targets for immunotherapy in ccRCC patients.

scholarly journals The Food Additive tBHQ Impairs NK Cell Cytotoxicity Against Influenza Infection (FS12-02-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Allison Boss ◽  
Robert Freeborn ◽  
Sheng Liu ◽  
Joseph Zagorski ◽  
Alexandra Turley ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Influenza Infection ◽  
Control Diet ◽  
Granzyme B ◽  
Influenza Virus Infection ◽  
Enzyme Linked Immunosorbent Assay ◽  
Activation Markers

Abstract Objectives We examined the effects of the food preservative, tert-Butylhydroquinone (tBHQ), on natural killer (NK) cells when infected with influenza in C57Bl/6 mice. Previously, we found tBHQ to negatively impact splenic NK cell effector function in vitro. Therefore, we hypothesized that the consumption of tBHQ would impair the NK cell response against a primary influenza virus infection. Methods Female, C57Bl/6 mice were fed either a diet containing 0.0014% tBHQ or a control diet two weeks prior to infection. Mice were instilled intranasally with 21.78 HAU of influenza A/PR/8/34 (H1N1) and were monitored for two days. Body weight was recorded as a measurement for infection. After day two of infection, lungs were collected and processed for analysis by flow cytometry, enzyme-linked immunosorbent assay (ELISA), and total antioxidant capacity (TAC). Results The NK cell activation markers, CD25 and CD69, were not affected by tBHQ consumption. Additionally, tBHQ did not have an effect on maturation of NK cells or interferon (IFN)γ production. Notably, NK cell expression of granzyme B was significantly decreased with tBHQ in infected mice. Furthermore, mice on the tBHQ diet showed decreased TAC after two days of infection compared to mice on the control diet, suggesting increased oxidative stress in the tBHQ group. Conclusions tBHQ had no effect on NK cell activation, maturation, and IFNγ production after two days of influenza infection. However, decreased expression of granzyme B by NK cells suggests tBHQ may impair NK cell cytoxicity during the infection. Moreover, the decrease in TAC suggests increased oxidative stress in the tBHQ-treated mice. Funding Sources This study was funded by National Institute of Environmental Health Sciences (ES024966).

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