Effects of BCG vaccination on donor unrestricted T cells in humans

SummaryAntigen classes other than proteins can be presented to T cells by near-monomorphic antigen-presenting molecules such as CD1, MR1, and butyrophilin 3A1. We sought to define the roles of donor unrestricted T (DURT) cells, including MR1-reactive MAIT cells, CD1b-reactive glucose monomycolate (GMM)-specific T cells, CD1d-reactive NKT cells, and γδ T cells, in vaccination against Mycobacterium tuberculosis. We characterized DURT cells following primary bacille Calmette-Guerin (BCG) vaccination in infants or BCG-revaccination in adults. BCG (re)vaccination did not modulate peripheral blood frequencies, T cell activation or memory profiles of MAIT cells, CD1b-restricted GMM-specific and germline-encoded mycolyl-reactive (GEM) cells or CD1d- restricted NKT cells. By contrast, BCG vaccination was associated with increased frequencies of γδ T cells as well as a novel subset of IFN-γ-expressing CD4+ T cells with a CD26+CD161+TRAV1-2− phenotype in infants. More studies are required to understand the full potential of DURT cells in new TB vaccine strategies.

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

10.1101/2021.08.21.21262399 ◽

2021 ◽

Author(s):

Jennifer R Habel ◽

Brendon Y Chua ◽

Lukasz Kedzierski ◽

Kevin J Selva ◽

Timon Damelang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Pregnant Women ◽

T Cell Activation ◽

Cell Activation ◽

Nk Cell ◽

Γδ T Cells ◽

Immunological Parameters ◽

Immunological Responses ◽

Mait Cells

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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Specialized subsets of innate-like T cells and dendritic cells protect from lethal pneumococcal infection in the lung

10.1101/2021.07.25.453697 ◽

2021 ◽

Author(s):

Mallory Paynich Murray ◽

Catherine M. Crosby ◽

Paola Marcovecchio ◽

Nadine Hartmann ◽

Shilpi Chandra ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell Activation ◽

Cell Activation ◽

Pneumococcal Infection ◽

Γδ T Cells ◽

Cellular Interactions ◽

Gm Csf ◽

Mait Cells ◽

Barrier Tissues

Innate-like T cells, including invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells and γδ T cells, are present in various barrier tissues, including the lung. They carry out protective responses during infections, but the mechanisms for protection are not completely understood. Here, we investigated their roles during pulmonary infection with Streptococcus pneumoniae. Following infection, innate-like T cells rapidly increased in lung tissue, in part through recruitment, but TCR activation and cytokine production occurred mostly in IL-17-producing NKT17 and γδ T cells. NKT17 cells were preferentially located outside the vasculature prior to infection, as were CD103+ dendritic cells (cDC1), which were important both for antigen presentation to NKT17 cells and γδ T cell activation. Whereas IL-17A-producing γδ T cells also were numerous, GM-CSF was exclusive to NKT17 cells and contributed to iNKT cell-mediated protection. These studies demonstrate how particular cellular interactions and responses of functional subsets of innate-like T cells contribute to protection from pathogenic lung infection.

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T-Bet Is Critical for the Development of Acute Graft-Versus-Host Disease By Regulating Hematopoietic Antigen Presenting Cells

Blood ◽

10.1182/blood.v124.21.846.846 ◽

2014 ◽

Vol 124 (21) ◽

pp. 846-846

Author(s):

Jianing Fu ◽

Yongxia Wu ◽

Hung Nguyen ◽

Jessica Lauren Heinrichs ◽

Steven Schutt ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Apoptosis ◽

Cell Activation ◽

T Cell Apoptosis ◽

Donor T Cells ◽

Ifn Γ ◽

Antigen Presenting

Abstract Graft-versus-host disease (GVHD) remains to be a major obstacle for the efficacy and continuing success of allogeneic hematopoietic stem cell transplantation in the treatment of various malignant and non-malignant diseases. Activation of antigen presenting cells (APCs), both host and donor origin, plays a crucial role in priming alloreactive donor T cells to induce and intensify acute GVHD (aGVHD). Beyond its critical effects on T cells, the T-box transcription factor T-bet also regulates activity of APCs, including dendritic cells (DCs) and B cells. However, the effect and mechanism of T-bet in regulating APCs in the development of aGVHD has not been investigated. To evaluate the role of T-bet in modulating APC function and aGVHD development, we compared the severity of aGVHD in WT versus T-bet-/- recipients using several well-defined, clinically relevant murine models of allogeneic bone marrow transplantation (allo-BMT). We observed that T-bet-/- recipients developed much milder aGVHD than their WT counterparts, reflected by significantly higher rate of survival, lower clinical scores, and better donor BM-derived B- and T-cell reconstitution. In T-bet-/- recipients, donor T cells significantly reduced IFN-γ production, proliferation and migration, and caused less damage in aGVHD target organs, such as liver and gut. By using various BM chimeras as the recipients, we further observed that T-bet expressed on recipient hematopoietic APCs was primarily responsible for donor T-cell response and pathogenicity in causing aGVHD. Additionally, we evaluated the role of T-bet in donor APCs by transplanting WT or T-bet-/- BM together with WT T cells into lethally irradiated allogeneic recipients. We observed that recipients of T-bet-/- BM developed attenuated aGVHD compared with those of WT BM, suggesting that T-bet also contributes to the function of donor APCs in the induction of GVHD. Given DCs are the most potent hematopoietic APCs, we subsequently focused on recipient DCs. DCs in T-bet-/- recipient produced less IFN-γ, expressed higher levels of Trail, but not FasL or TNF, to induce significantly higher levels of apoptosis on donor T cells prior to their massive proliferation. To test whether Trail/DR5 interaction is responsible for the induction of donor T cell apoptosis and subsequent reduction of aGVHD in T-bet-/- recipients, we compared the ability of WT or DR5-/- T cells in inducing aGVHD in WT versus T-bet-/- recipients after allo-BMT. While WT T cells induced severe aGVHD in WT recipients, they failed to do in T-bet-/- recipients. In contrast, DR5-/- donor T cells were capable to induce severe aGVHD in the recipients regardless of T-bet expression. These data suggests that Trail/DR5 interaction is a major signaling pathway responsible for donor T-cell apoptosis induced by T-bet-/- APCs, through which alleviates the development of aGVHD. In conclusion, we demonstrate that T-bet up-regulates IFN-γ production and down-regulates Trail expression on recipient DCs, which promotes donor T-cell activation and mitigates T-cell apoptosis, respectively. Thus, T-bet plays a critical role in the development of aGVHD by regulating the activity of hematopoietic APCs, particularly DCs. Taken together with our previous findings, we propose that T-bet is a potential therapeutic target for the control of aGVHD through regulating T-cell activation and differentiation as well as APC functions. Disclosures No relevant conflicts of interest to declare.

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Kinetics of the Immune Response Profile in Guinea Pigs after Vaccination with Mycobacterium bovis BCG and Infection with Mycobacterium tuberculosis

Infection and Immunity ◽

10.1128/iai.00704-09 ◽

2009 ◽

Vol 77 (11) ◽

pp. 4837-4846 ◽

Cited By ~ 18

Author(s):

Ajay Grover ◽

Jennifer Taylor ◽

JoLynn Troudt ◽

Andrew Keyser ◽

Kimberly Arnett ◽

...

Keyword(s):

T Cells ◽

Mrna Expression ◽

Mycobacterium Bovis ◽

T Cell Activation ◽

Guinea Pigs ◽

Cell Activation ◽

Activated T Cells ◽

Bcg Vaccination ◽

Tnf Α ◽

Ifn Γ

ABSTRACT The guinea pig model of tuberculosis is used extensively in assessing novel vaccines, since Mycobacterium bovis BCG vaccination effectively prolongs survival after low-dose aerosol infection with virulent M. tuberculosis. To better understand how BCG extends time to death after pulmonary infection with M. tuberculosis, we examined cytokine responses postvaccination and recruitment of activated T cells and cytokine response postinfection. At 10 weeks postvaccination, splenic gamma interferon (IFN-γ) mRNA was significantly elevated compared to the levels at 5 weeks in ex vivo stimulation assays. At 15, 40, 60, and 120 days postinfection, T-cell activation (CD4+ CD62Llow and CD8+ CD62Llow) and mRNA expression of IFN-γ, tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), IL-10, IL-12, and eomesodermin were assessed. Our data show that at day 40, BCG-vaccinated guinea pigs had significantly increased levels of IFN-γ mRNA expression but decreased TNF-α mRNA expression in their lungs compared to the levels in nonvaccinated animals. At day 120, a time when nonvaccinated guinea pigs succumbed to infection, low levels of IFN-γ mRNA were observed even though there were increasing levels of IL-1, IL-12, and IL-10, and the numbers of activated T cells did not differ from those in BCG-vaccinated animals. BCG vaccination conferred the advantage of recruiting greater numbers of CD4+ CD62Llow T cells at day 40, although the numbers of CD8+ CD62Llow T cells were not elevated compared to the numbers in nonvaccinated animals. Our data suggest that day 40 postinfection may be a pivotal time point in determining vaccine efficacy and prolonged survival and that BCG promotes the capacity of T cells in the lungs to respond to infection.

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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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Activation of Human γδ T Cells: Modulation by Toll-Like Receptor 8 Ligands and Role of Monocytes

Cells ◽

10.3390/cells9030713 ◽

2020 ◽

Vol 9 (3) ◽

pp. 713 ◽

Cited By ~ 4

Author(s):

Ruben Serrano ◽

Daniela Wesch ◽

Dieter Kabelitz

Keyword(s):

T Cells ◽

T Cell ◽

Zoledronic Acid ◽

T Cell Activation ◽

Cell Activation ◽

Γδ T Cells ◽

Γδ T Cell ◽

Toll Like Receptor ◽

Tnf Α ◽

Ifn Γ

Background: Human Vγ9Vδ2 γδ T cells can kill a variety of cancer cells and have attracted substantial interest for cancer immunotherapy. Toll-like receptor (TLR) ligands are promising adjuvants for cancer immunotherapy, but TLR7/8 ligand Resiquimod has been shown to inhibit CD4 T-cell activation in a monocyte-dependent manner. Therefore, we studied the modulation of human γδ T-cell activation by TLR7/8 ligands. Methods: Peripheral blood mononuclear cells (PBMC) or purified γδ T cells together with purified monocytes were stimulated with zoledronic acid or phosphoantigens in the absence or presence of various imidazoquinoline TLR7 or TLR8 agonists. Read-out systems included interferon-γ induction and cellular expansion of γδ T cells, as well as viability, cell surface antigen modulation, and IL-1β and TNF-α production of monocytes. Results: TLR8 ligand TL8-506 and TLR7/8 ligand Resiquimod (but not TLR7 ligands) rapidly induced IFN-γ expression in γδ T cells within PBMC, and co-stimulated phosphoantigen-induced IFN-γ expression in γδ T cells. On the other hand, TLR8 ligands potently suppressed γδ T-cell expansion in response to zoledronic acid and phosphoantigen. Purified monocytes secreted large amounts of IL-1β and TNF-α when stimulated with TLR8 ligands but simultaneously underwent substantial cell death after 24 h. Conclusions: TLR8 ligand-activated monocytes potently co-stimulate early γδ T-cell activation but failed to provide accessory cell function for in vitro expansion of γδ T cells.

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Cryopreservation of Whole Tumor Biopsies from Rectal Cancer Patients Enable Phenotypic and In Vitro Functional Evaluation of Tumor-Infiltrating T Cells

Cancers ◽

10.3390/cancers13102428 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2428

Author(s):

Frank Liang ◽

Azar Rezapour ◽

Peter Falk ◽

Eva Angenete ◽

Ulf Yrlid

Keyword(s):

Rectal Cancer ◽

T Cells ◽

Γδ T Cells ◽

T Cell Subsets ◽

Functional Evaluation ◽

Mait Cells ◽

Ifn Γ ◽

Tumor Biopsies

TILs comprise functionally distinct conventional and unconventional T cell subsets and their role in responses to CRC treatments is poorly understood. We explored recovery of viable TILs from cryopreserved tumor biopsies of (chemo)-radiated patients with rectal cancer to establish a platform for retrospective TIL analyses of frozen tumors from pre-selected study cohorts. Frequencies of TIL subsets and their capacity to mount IFN-γ responses in cell suspensions of fresh vs. cryopreserved portions of the same tumor biopsies were determined for platform validation. The percentages and proportions of CD4+ TILs and CD8+ cytotoxic T lymphocytes (CTLs) among total TILs were not affected by cryopreservation. While recovery of unconventional γδ T cells and mucosal-associated invariant T cells (MAIT cells) was stable after cryopreservation, the regulatory T cells (Tregs) were reduced, but in sufficient yields for quantification. IFN-γ production by in vitro-stimulated CD4+ TILs, CTLs, γδ T cells, and MAIT cells were proportionally similar in fresh and cryopreserved tumor portions, albeit the latter displayed lower levels. Thus, the proposed platform intended for TIL analyses on cryopreserved tumor biobank biopsies holds promises for studies linking the quantity and quality of TIL subsets with specific clinical outcome after CRC treatment.

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CCL19 enhances CD8+ T-cell responses and accelerates HBV clearance

Journal of Gastroenterology ◽

10.1007/s00535-021-01799-8 ◽

2021 ◽

Author(s):

Yan Yan ◽

Wei Zhao ◽

Wei Liu ◽

Yan Li ◽

Xu Wang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Crucial Role ◽

Cell Activation ◽

Hbv Infection ◽

Host Immune System ◽

Tnf Α ◽

Ifn Γ ◽

High Level

Abstract Background Chemokine (C–C motif) ligand 19 (CCL19) is a leukocyte chemoattractant that plays a crucial role in cell trafficking and leukocyte activation. Dysfunctional CD8+ T cells play a crucial role in persistent HBV infection. However, whether HBV can be cleared by CCL19-activated immunity remains unclear. Methods We assessed the effects of CCL19 on the activation of PBMCs in patients with HBV infection. We also examined how CCL19 influences HBV clearance and modulates HBV-responsive T cells in a mouse model of chronic hepatitis B (CHB). In addition, C–C chemokine-receptor type 7 (CCR7) knockdown mice were used to elucidate the underlying mechanism of CCL19/CCR7 axis-induced immune activation. Results From in vitro experiments, we found that CCL19 enhanced the frequencies of Ag-responsive IFN-γ+ CD8+ T cells from patients by approximately twofold, while CCR7 knockdown (LV-shCCR7) and LY294002 partially suppressed IFN-γ secretion. In mice, CCL19 overexpression led to rapid clearance of intrahepatic HBV likely through increased intrahepatic CD8+ T-cell proportion, decreased frequency of PD-1+ CD8+ T cells in blood and compromised suppression of hepatic APCs, with lymphocytes producing a significantly high level of Ag-responsive TNF-α and IFN-γ from CD8+ T cells. In both CCL19 over expressing and CCR7 knockdown (AAV-shCCR7) CHB mice, the frequency of CD8+ T-cell activation-induced cell death (AICD) increased, and a high level of Ag-responsive TNF-α and low levels of CD8+ regulatory T (Treg) cells were observed. Conclusions Findings in this study provide insights into how CCL19/CCR7 axis modulates the host immune system, which may promote the development of immunotherapeutic strategies for HBV treatment by overcoming T-cell tolerance.

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