Integrated immune networks in SARS-CoV-2 infected pregnant women reveal differential NK cell and unconventional T cell activation

ABSTRACTAlthough pregnancy poses a greater risk for severe COVID-19, the underlying immunological changes associated with SARS-CoV-2 infection during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in pregnant and non-pregnant women during acute and convalescent COVID-19 up to 258 days post symptom onset, quantifying 217 immunological parameters. Additionally, matched maternal and cord blood were collected from COVID-19 convalescent pregnancies. Although serological responses to SARS-CoV-2 were similar in pregnant and non-pregnant women, cellular immune analyses revealed marked differences in key NK cell and unconventional T cell responses during COVID-19 in pregnant women. While NK cells, γδ T cells and MAIT cells displayed pre-activated phenotypes in healthy pregnant women when compared to non-pregnant age-matched women, activation profiles of these pre-activated NK and unconventional T cells remained unchanged at acute and convalescent COVID-19 in pregnancy. Conversely, activation dynamics of NK and unconventional T cells were prototypical in non-pregnant women in COVID-19. In contrast, activation of αβ CD4+ and CD8+ T cells, T follicular helper cells and antibody-secreting cells was similar in pregnant and non-pregnant women with COVID-19. Elevated levels of IL-1β, IFN-γ, IL-8, IL-18 and IL-33 were also found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, our study provides the first comprehensive map of longitudinal immunological responses to SARS-CoV-2 infection in pregnant women, providing insights into patient management and education during COVID-19 pregnancy.

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Integrated immune networks in SARS-CoV-2 infected pregnant women reveal differential NK cell and unconventional T cell activation

10.21203/rs.3.rs-745648/v1 ◽

2021 ◽

Author(s):

Katherine Kedzierska ◽

Jennifer Habel ◽

Brendon Chua ◽

Lukasz Kedzierski ◽

Kevin Selva ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Pregnant Women ◽

T Cell Activation ◽

Cell Activation ◽

Nk Cell ◽

Γδ T Cells ◽

Immunological Parameters ◽

Immunological Responses ◽

Mait Cells

Abstract Although pregnancy poses a greater risk for severe COVID-19, the underlying immunological changes associated with SARS-CoV-2 infection during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in pregnant and non-pregnant women during acute and convalescent COVID-19 up to 258 days post symptom onset, quantifying 217 immunological parameters. Additionally, matched maternal and cord blood were collected from COVID-19 convalescent pregnancies. Although serological responses to SARS-CoV-2 were similar in pregnant and non-pregnant women, cellular immune analyses revealed marked differences in key NK cell and unconventional T cell responses during COVID-19 in pregnant women. While NK, γδ T cells and MAIT cells displayed pre-activated phenotypes in healthy pregnant women when compared to non-pregnant age-matched women, activation profiles of these pre-activated NK and unconventional T cells remained unchanged at acute and convalescent COVID-19 in pregnancy. Conversely, activation dynamics of NK and unconventional T cells were prototypical in non-pregnant women in COVID-19. In contrast, activation of αβ CD4+ and CD8+ T cells, T follicular helper cells and antibody-secreting cells was similar in pregnant and non-pregnant women with COVID-19. Elevated levels of IL-1β, IFN-γ, IL-8, IL-18 and IL-33 were also found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, our study provides the first comprehensive map of longitudinal immunological responses to SARS-CoV-2 infection in pregnant women, providing insights into patient management and education during COVID-19 pregnancy.

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γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation

Cell ◽

10.1016/j.cell.2020.10.041 ◽

2020 ◽

Vol 183 (4) ◽

pp. 1134-1136

Author(s):

Donnele Daley ◽

Constantinos Pantelis Zambirinis ◽

Lena Seifert ◽

Neha Akkad ◽

Navyatha Mohan ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Γδ T Cells

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γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation

Cell ◽

10.1016/j.cell.2016.07.046 ◽

2016 ◽

Vol 166 (6) ◽

pp. 1485-1499.e15 ◽

Cited By ~ 132

Author(s):

Donnele Daley ◽

Constantinos Pantelis Zambirinis ◽

Lena Seifert ◽

Neha Akkad ◽

Navyatha Mohan ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Γδ T Cells

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107 Effects of IL-2 and IL-15 on the proliferative and antitumor capacities of allogeneic CD20 CAR-engineered γδ T cells in a 3D B cell lymphoma spheroid assay

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0107 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A119-A119

Author(s):

Lu Bai ◽

Kevin Nishimoto ◽

Mustafa Turkoz ◽

Marissa Herrman ◽

Jason Romero ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cytokine Production ◽

Γδ T Cells ◽

Γδ T Cell ◽

Car T

BackgroundAutologous chimeric antigen receptor (CAR) T cells have been shown to be efficacious for the treatment of B cell malignancies; however, widespread adoption and application of CAR T cell products still face a number of challenges. To overcome these challenges, Adicet Bio is developing an allogeneic γδ T cell-based CAR T cell platform, which capitalizes on the intrinsic abilities of Vδ1 γδ T cells to recognize and kill transformed cells in an MHC-unrestricted manner, to migrate to epithelial tissues, and to function in hypoxic conditions. To gain a better understanding of the requirements for optimal intratumoral CAR Vδ1 γδ T cell activation, proliferation, and differentiation, we developed a three-dimensional (3D) tumor spheroid assay, in which tumor cells acquire the structural organization of a solid tumor and establish a microenvironment that has oxygen and nutrient gradients. Moreover, through the addition of cytokines and/or tumor stromal cell types, the spheroid microenvironment can be modified to reflect hot or cold tumors. Here, we report on the use of a 3D CD20+ Raji lymphoma spheroid assay to evaluate the effects of IL-2 and IL-15, positive regulators of T cell homeostasis and differentiation, on the proliferative and antitumor capacities of CD20 CAR Vδ1 γδ T cells.MethodsMolecular, phenotypic, and functional profiling were performed to characterize the in vitro dynamics of the intraspheroid CD20 CAR Vδ1 γδ T cell response to target antigen in the presence of IL-2, IL-15, or no added cytokine.ResultsWhen compared to no added cytokine, the addition of IL-2 or IL-15 enhanced CD20 CAR Vδ1 γδ T cell activation, proliferation, survival, and cytokine production in a dose-dependent manner but were only able to alter the kinetics of Raji cell killing at low effector to target ratios. Notably, differential gene expression analysis using NanoString nCounter® Technology confirmed the positive effects of IL-2 or IL-15 on CAR-activated Vδ1 γδ T cells as evidenced by the upregulation of genes involved in activation, cell cycle, mitochondrial biogenesis, cytotoxicity, and cytokine production.ConclusionsTogether, these results not only show that the addition of IL-2 or IL-15 can potentiate CD20 CAR Vδ1 γδ T cell activation, proliferation, survival, and differentiation into antitumor effectors but also highlight the utility of the 3D spheroid assay as a high throughput in vitro method for assessing and predicting CAR Vδ1 γδ T cell activation, proliferation, survival, and differentiation in hot and cold tumors.

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Abstract P347: γδ T Cells Drive CD4 + And CD8 + T Cell Activation In Hypertension

Hypertension ◽

10.1161/hyp.70.suppl_1.p347 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Antoine Caillon ◽

Pierre Paradis ◽

Ernesto L Schiffrin

Keyword(s):

T Cells ◽

T Cell ◽

T Lymphocytes ◽

Vascular Injury ◽

T Cell Activation ◽

Cell Activation ◽

Γδ T Cells ◽

Ang Ii ◽

Adaptive Immune Cells ◽

Induced Hypertension

Objective: Both innate (monocyte/macrophages) and adaptive immune cells (T lymphocytes) have been shown to play a role in the development of vascular injury in hypertension. Recently, we demonstrated that a small subset of “innate-like” T lymphocytes, expressing the γ/δ T cell receptor (TCR) rather than the αβ TCR, plays a key role in hypertension and vascular injury. We demonstrated an increased number and activation (CD69 + ) of γδ T cells during the development of hypertension caused by angiotensin (Ang) II infusion, and that deficiency in γδ T cells prevented Ang II-induced hypertension, resistance artery endothelial dysfunction and spleen T-cell activation in mice. We hypothesized that γδ T cells mediate activation of other T cells in hypertension. Method and Results: Fourteen to 15-week old male C57BL/6 wild-type (WT) mice were infused with Ang II (490 ng/kg/min, SC) for 3, 7 and 14 days (n=5-7) and spleen T cell profile was determined by flow cytometry. A correlation was demonstrated between the frequency (FREQ) and the number (#) of activated CD69 + γδ T cells and CD4 + CD69 + T cells (FREQ: r=0.41, P <0.05 and #: r=0.58, P <0.001) and CD8 + CD69 + T cells (FREQ: r=0.36, P <0.05 and #: r=0.50, P <0.01). We also demonstrated a high correlation between the # of CD69 + γδ T cells expressing CD27, a marker of interferon-γ expressing cells and a member of the T-T interaction molecules, with CD4 + CD69 + (r=0.88, P <0.001) and CD8 + CD69 + (r=0.81, P <0.01) T cells after 7 days of Ang II infusion. Conclusion: This study demonstrated an association between CD27 + CD69 + γδ T cells and activated T cells. These results suggest that γδ T cells drive activation of other T cells in Ang II-induced hypertension. Targeting γδ T cells may contribute to reduce inflammation in hypertension.

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Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates

Blood ◽

10.1182/blood-2010-03-275438 ◽

2010 ◽

Vol 116 (17) ◽

pp. 3238-3248 ◽

Cited By ~ 72

Author(s):

Enrico Lugli ◽

Carolyn K. Goldman ◽

Liyanage P. Perera ◽

Jeremy Smedley ◽

Rhonda Pung ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Nk Cells ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

Nk Cell ◽

The Body ◽

Effector Memory ◽

Memory Cd8 T Cells

Abstract Interleukin-15 (IL-15) is a cytokine with potential therapeutic application in individuals with cancer or immunodeficiency to promote natural killer (NK)– and T-cell activation and proliferation or in vaccination protocols to generate long-lived memory T cells. Here we report that 10-50 μg/kg IL-15 administered intravenously daily for 12 days to rhesus macaques has both short- and long-lasting effects on T-cell homeostasis. Peripheral blood lymphopenia preceded a dramatic expansion of NK cells and memory CD8 T cells in the circulation, particularly a 4-fold expansion of central memory CD8 T cells and a 6-fold expansion of effector memory CD8 T cells. This expansion is a consequence of their activation in multiple tissues. A concomitant inverted CD4/CD8 T-cell ratio was observed throughout the body at day 13, a result of preferential CD8 expansion. Expanded T- and NK-cell populations declined in the blood soon after IL-15 was stopped, suggesting migration to extralymphoid sites. By day 48, homeostasis appears restored throughout the body, with the exception of the maintenance of an inverted CD4/CD8 ratio in lymph nodes. Thus, IL-15 generates a dramatic expansion of short-lived memory CD8 T cells and NK cells in immunocompetent macaques and has long-term effects on the balance of CD4+ and CD8+ T cells.

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Butyrophilin 2A1 is essential for phosphoantigen reactivity by γδ T cells

Science ◽

10.1126/science.aay5516 ◽

2020 ◽

Vol 367 (6478) ◽

pp. eaay5516 ◽

Cited By ~ 62

Author(s):

Marc Rigau ◽

Simone Ostrouska ◽

Thomas S. Fulford ◽

Darryl N. Johnson ◽

Katherine Woods ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

T Cell Receptors ◽

Protective Immunity ◽

Cell Activation ◽

Molecular Targets ◽

Γδ T Cells ◽

Γδ T Cell ◽

Gamma Delta

Gamma delta (γδ) T cells are essential to protective immunity. In humans, most γδ T cells express Vγ9Vδ2+ T cell receptors (TCRs) that respond to phosphoantigens (pAgs) produced by cellular pathogens and overexpressed by cancers. However, the molecular targets recognized by these γδTCRs are unknown. Here, we identify butyrophilin 2A1 (BTN2A1) as a key ligand that binds to the Vγ9+ TCR γ chain. BTN2A1 associates with another butyrophilin, BTN3A1, and these act together to initiate responses to pAg. Furthermore, binding of a second ligand, possibly BTN3A1, to a separate TCR domain incorporating Vδ2 is also required. This distinctive mode of Ag-dependent T cell activation advances our understanding of diseases involving pAg recognition and creates opportunities for the development of γδ T cell–based immunotherapies.

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Faculty Opinions recommendation of γδ T cells support pancreatic oncogenesis by restraining αβ T cell activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726694346.793532510 ◽

2017 ◽

Author(s):

Dieter Kabelitz

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Γδ T Cells

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Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy

Blood ◽

10.1182/blood.2021011532 ◽

2021 ◽

Author(s):

Melissa M Berrien-Elliott ◽

Michelle Becker-Hapak ◽

Amanda F. Cashen ◽

Miriam T. Jacobs ◽

Pamela Wong ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

Nk Cells ◽

T Cell Activation ◽

Cell Activation ◽

Nk Cell ◽

Cd8 T Cell ◽

Clinical Activity ◽

Allogeneic Cell

NK cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from two independent clinical trial cohorts treated with MHC-haploidentical NK cell therapy for relapsed/refractory AML revealed that cytokine support by systemic IL-15 (N-803) resulted in reduced clinical activity, compared to IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+ T cell numbers in patients treated with IL-15/N-803, compared to IL2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T cell activation and proliferation, compared to IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived ML NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15.

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