scholarly journals Th1/Th17 T cell Tissue-Resident Immunity Increases Protection, But Is Not Required in a Vaccine Strategy Against Genital Infection With Chlamydia trachomatis

2021 ◽  
Vol 12 ◽  
Author(s):  
Nina Dieu Nhien Tran Nguyen ◽  
Safia Guleed ◽  
Anja Weinreich Olsen ◽  
Frank Follmann ◽  
Jan Pravsgaard Christensen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chlamydia Trachomatis ◽  
Post Infection ◽  
Genital Tract ◽  
T Cell Response ◽  
Mucosal Vaccine ◽  
Vaccine Strategy ◽  
Cell Immunity ◽  
Repeated Infections

The requirement for vaccine-induced tissue-resident immunity for protection against one or repeated infections with Chlamydia trachomatis (C.t.) is still not fully resolved. In this study, our aim was to investigate to which degree tissue-resident Th1/Th17 T cells in the genital tract (GT) could add to the protection mediated by circulating immunity. Out of several mucosal vaccine strategies, a strategy termed SIM (for simultaneous intrauterine and parenteral immunization with CAF01 adjuvanted CTH522), was superior in generating genital tract tissue-resident Th1/Th17 T cell immunity. This led to a faster and stronger local CD4 T cell response post infection, consisting of multifunctional IFNγ/TNFα-producing Th1 T cells and IFNγ/TNFα/IL-17-producing Th17 T cells, and a faster recruitment of innate immune cells. Post infection, SIM animals showed an additional significant reduction in bacterial levels compared to mice having received only a parenteral vaccine. Nevertheless, the parenteral strategy reduced bacterial levels by 75%, and interestingly, post infection, these mice generated their own vaccine-derived genital tract tissue-resident memory Th1/Th17 T cells, which upon a subsequent infection showed as fast an activation in the genital tract, as observed in SIM mice. Furthermore, in contrast to after the first infection, both groups of mice now showed a similar infection-induced boost in local vaginal IgA and IgG titers. Thus, vaccine-induced resident immunity, generated pre-infection, led to an advantage in the response against the first infection, but not the second infection, suggesting that a parenteral vaccine strategy is a suitable vaccine strategy against infections with Chlamydia trachomatis.

scholarly journals Mechanisms that allow vaccination against an oncolytic vesicular stomatitis virus-encoded transgene to enhance safety without abrogating oncolysis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Amanda W. K. AuYeung ◽  
Robert C. Mould ◽  
Ashley A. Stegelmeier ◽  
Jacob P. van Vloten ◽  
Khalil Karimi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vesicular Stomatitis Virus ◽  
Cell Response ◽  
Viral Infections ◽  
T Cell Response ◽  
Oncolytic Viruses ◽  
Oncolytic Virotherapy ◽  
Cell Immunity ◽  
Vesicular Stomatitis

AbstractVaccination can prevent viral infections via virus-specific T cells, among other mechanisms. A goal of oncolytic virotherapy is replication of oncolytic viruses (OVs) in tumors, so pre-existing T cell immunity against an OV-encoded transgene would seem counterproductive. We developed a treatment for melanomas by pre-vaccinating against an oncolytic vesicular stomatitis virus (VSV)-encoded tumor antigen. Surprisingly, when the VSV-vectored booster vaccine was administered at the peak of the primary effector T cell response, oncolysis was not abrogated. We sought to determine how oncolysis was retained during a robust T cell response against the VSV-encoded transgene product. A murine melanoma model was used to identify two mechanisms that enable this phenomenon. First, tumor-infiltrating T cells had reduced cytopathic potential due to immunosuppression. Second, virus-induced lymphopenia acutely removed virus-specific T cells from tumors. These mechanisms provide a window of opportunity for replication of oncolytic VSV and rationale for a paradigm change in oncolytic virotherapy, whereby immune responses could be intentionally induced against a VSV-encoded melanoma-associated antigen to improve safety without abrogating oncolysis.

scholarly journals TCR Repertoire Characterization for T Cells Expanded in Response to hRSV Infection in Mice Immunized with a Recombinant BCG Vaccine

Viruses ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 233
Author(s):  
Emma Rey-Jurado ◽  
Karen Bohmwald ◽  
Hernán G. Correa ◽  
Alexis M. Kalergis
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Response ◽  
Bcg Vaccine ◽  
Lung Damage ◽  
Cell Repertoire ◽  
Cell Immunity ◽  
Tcr Repertoire ◽  
Syncytial Virus

T cells play an essential role in the immune response against the human respiratory syncytial virus (hRSV). It has been described that both CD4+ and CD8+ T cells can contribute to the clearance of the virus during an infection. However, for some individuals, such an immune response can lead to an exacerbated and detrimental inflammatory response with high recruitment of neutrophils to the lungs. The receptor of most T cells is a heterodimer consisting of α and β chains (αβTCR) that upon antigen engagement induces the activation of these cells. The αβTCR molecule displays a broad sequence diversity that defines the T cell repertoire of an individual. In our laboratory, a recombinant Bacille Calmette–Guérin (BCG) vaccine expressing the nucleoprotein (N) of hRSV (rBCG-N-hRSV) was developed. Such a vaccine induces T cells with a Th1 polarized phenotype that promote the clearance of hRSV infection without causing inflammatory lung damage. Importantly, as part of this work, the T cell receptor (TCR) repertoire of T cells expanded after hRSV infection in naïve and rBCG-N-hRSV-immunized mice was characterized. A more diverse TCR repertoire was observed in the lungs from rBCG-N-hRSV-immunized as compared to unimmunized hRSV-infected mice, suggesting that vaccination with the recombinant rBCG-N-hRSV vaccine triggers the expansion of T cell populations that recognize more viral epitopes. Furthermore, differential expansion of certain TCRVβ chains was found for hRSV infection (TCRVβ+8.3 and TCRVβ+5.1,5.2) as compared to rBCG-N-hRSV vaccination (TCRVβ+11 and TCRVβ+12). Our findings contribute to better understanding the T cell response during hRSV infection, as well as the functioning of a vaccine that induces a protective T cell immunity against this virus.

scholarly journals Gamma Interferon Is Required for Chlamydia Clearance but Is Dispensable for T Cell Homing to the Genital Tract

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Jennifer D. Helble ◽  
Rodrigo J. Gonzalez ◽  
Ulrich H. von Andrian ◽  
Michael N. Starnbach
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Chlamydia Trachomatis ◽  
Genital Tract ◽  
Gamma Interferon ◽  
Cell Homing ◽  
Content Type ◽  
T Cell Homing ◽  
Ifn Γ

ABSTRACT While there is no effective vaccine against Chlamydia trachomatis infection, previous work has demonstrated the importance of C. trachomatis-specific CD4+ T cells (NR1 T cells) in pathogen clearance. Specifically, NR1 T cells have been shown to be protective in mice, and this protection depends on the host’s ability to sense the cytokine gamma interferon (IFN-γ). However, it is unclear what role NR1 production or sensing of IFN-γ plays in T cell homing to the genital tract or T cell-mediated protection against C. trachomatis. Using two-photon microscopy and flow cytometry, we found that naive wild-type (WT), IFN-γ−/−, and IFN-γR−/− NR1 T cells specifically home to sections in the genital tract that contain C. trachomatis. We also determined that protection against infection requires production of IFN-γ from either NR1 T cells or endogenous cells, further highlighting the importance of IFN-γ in clearing C. trachomatis infection. IMPORTANCE Chlamydia trachomatis is an important mucosal pathogen that is the leading cause of sexually transmitted bacterial infections in the United States. Despite this, there is no vaccine currently available. In order to develop such a vaccine, it is necessary to understand the components of the immune response that can lead to protection against this pathogen. It is well known that antigen-specific CD4+ T cells are critical for Chlamydia clearance, but the contexts in which they are protective or not protective are unknown. Here, we aimed to characterize the importance of gamma interferon production and sensing by T cells and the effects on the immune response to C. trachomatis. Our work here helps to define the contexts in which antigen-specific T cells can be protective, which is critical to our ability to design an effective and protective vaccine against C. trachomatis.

scholarly journals Key role of T cell defects in age-related vulnerability to West Nile virus

2009 ◽  
Vol 206 (12) ◽  
pp. 2735-2745 ◽  
Author(s):  
James D. Brien ◽  
Jennifer L. Uhrlaub ◽  
Alec Hirsch ◽  
Clayton A. Wiley ◽  
Janko Nikolich-Žugich
Keyword(s):  
T Cells ◽  
West Nile Virus ◽  
T Cell ◽  
Cd8 T Cells ◽  
The Elderly ◽  
T Cell Response ◽  
West Nile ◽  
Immunodeficient Mice ◽  
Age Related ◽  
Cell Immunity

West Nile virus (WNV) infection causes a life-threatening meningoencephalitis that becomes increasingly more prevalent over the age of 50 and is 40–50× more prevalent in people over the age of 70, compared with adults under the age of 40. In a mouse model of age-related vulnerability to WNV, we demonstrate that death correlates with increased viral titers in the brain and that this loss of virus control with age was the result of defects in the CD4 and CD8 T cell response against WNV. Specific age-related defects in T cell responses against dominant WNV epitopes were detected at the level of cytokine and lytic granule production, each of which are essential for resistance against WNV, and in the ability to generate multifunctional anti-WNV effector T cells, which are believed to be critical for robust antiviral immunity. In contrast, at the peak of the response, old and adult T cells exhibited superimposable peptide sensitivity. Most importantly, although the adult CD4 or CD8 T cells readily protected immunodeficient mice upon adoptive transfer, old T cells of either subset were unable to provide WNV-specific protection. Consistent with a profound qualitative and quantitative defect in T cell immunity, old brains contained at least 12× fewer total effector CD8 T cells compared with adult mice at the peak of brain infection. These findings identify potential targets for immunomodulation and treatment to combat lethal WNV infection in the elderly.

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 Targeting of Cdc42 GTPase in regulatory T cells unleashes anti-tumor T cell immunity

2021 ◽  
Author(s):  
Khalid W Kalim ◽  
Jun-Qi Yang ◽  
Mark Wunderlich ◽  
Vishnu Modur ◽  
Phuong Nguyen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treg Cell ◽  
Cell Function ◽  
Treg Cells ◽  
T Cell Response ◽  
T Cell Immunity ◽  
Cell Plasticity ◽  
Effector T Cell ◽  
Cell Immunity

Regulatory T (Treg) cells play an important role in maintaining immune tolerance through inhibiting effector T cell function. In the tumor microenvironment, Treg cells are utilized by tumor cells to counteract effector T cell-mediated tumor killing. Targeting Treg cells may thus unleash the anti-tumor activity of effector T cells. While systemic depletion of Treg cells can cause excessive effector T cell responses and subsequent autoimmune diseases, controlled targeting of Treg cells may benefit cancer patients. Here we show that Treg cell-specific heterozygous deletion or pharmacological targeting of Cdc42 GTPase does not affect Treg cell numbers but induces Treg cell plasticity, leading to anti-tumor T cell immunity without detectable autoimmune reactions. Cdc42 targeting potentiates an immune checkpoint blocker anti-PD-1 antibody-mediated T cell response against mouse and human tumors. Mechanistically, Cdc42 targeting induces Treg cell plasticity and unleashes anti-tumor T cell immunity through carbonic anhydrase I-mediated pH changes. Thus, rational targeting of Cdc42 in Treg cells holds therapeutic promises in cancer immunotherapy.

scholarly journals Alloantigen-activated (AAA) CD4+ T cells reinvigorate host endogenous T cell immunity to eliminate pre-established tumors in mice

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Kazuhiro Mochizuki ◽  
Shogo Kobayashi ◽  
Nobuhisa Takahashi ◽  
Kotaro Sugimoto ◽  
Hideki Sano ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Antitumor Immunity ◽  
Unmet Need ◽  
T Cell Response ◽  
Hematopoietic Stem ◽  
Cell Immunity ◽  
Allogeneic Lymphocytes

Abstract Background Cancer vaccines that induce endogenous antitumor immunity represent an ideal strategy to overcome intractable cancers. However, doing this against a pre-established cancer using autologous immune cells has proven to be challenging. “Allogeneic effects” refers to the induction of an endogenous immune response upon adoptive transfer of allogeneic lymphocytes without utilizing hematopoietic stem cell transplantation. While allogeneic lymphocytes have a potent ability to activate host immunity as a cell adjuvant, novel strategies that can activate endogenous antitumor activity in cancer patients remain an unmet need. In this study, we established a new method to destroy pre-developed tumors and confer potent antitumor immunity in mice using alloantigen-activated CD4+ (named AAA-CD4+) T cells. Methods AAA-CD4+ T cells were generated from CD4+ T cells isolated from BALB/c mice in cultures with dendritic cells (DCs) induced from C57BL/6 (B6) mice. In this culture, allogeneic CD4+ T cells that recognize and react to B6 mouse-derived alloantigens are preferentially activated. These AAA-CD4+ T cells were directly injected into the pre-established melanoma in B6 mice to assess their ability to elicit antitumor immunity in vivo. Results Upon intratumoral injection, these AAA-CD4+ T cells underwent a dramatic expansion in the tumor and secreted high levels of IFN-γ and IL-2. This was accompanied by markedly increased infiltration of host-derived CD8+ T cells, CD4+ T cells, natural killer (NK) cells, DCs, and type-1 like macrophages. Selective depletion of host CD8+ T cells, rather than NK cells, abrogated this therapeutic effect. Thus, intratumoral administration of AAA-CD4+ T cells results in a robust endogenous CD8+ T cell response that destroys pre-established melanoma. This locally induced antitumor immunity elicited systemic protection to eliminate tumors at distal sites, persisted over 6 months in vivo, and protected the animals from tumor re-challenge. Notably, the injected AAA-CD4+ T cells disappeared within 7 days and caused no adverse reactions. Conclusions Our findings indicate that AAA-CD4+ T cells reinvigorate endogenous cytotoxic T cells to eradicate pre-established melanoma and induce long-term protective antitumor immunity. This approach can be immediately applied to patients with advanced melanoma and may have broad implications in the treatment of other types of solid tumors.

scholarly journals The SARS-CoV-2 T-cell immunity is directed against the spike, membrane, and nucleocapsid protein and associated with COVID 19 severity

2020 ◽  
Author(s):  
Constantin J Thieme ◽  
Moritz Anft ◽  
Krystallenia Paniskaki ◽  
Arturo Blazquez-Navarro ◽  
Adrian Doevelaar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Severe Infection ◽  
T Cell Response ◽  
Cell Responses ◽  
Interindividual Variations ◽  
Cell Immunity ◽  
M Proteins ◽  
Critical Patients ◽  
N Proteins

Identification of immunogenic targets of SARS-CoV-2 is crucial for monitoring of antiviral immunity and vaccine design. Currently, mainly anti-spike (S)-protein adaptive immunity is investigated. However, also the nucleocapsid (N)- and membrane (M)-proteins should be considered as diagnostic and prophylactic targets. The aim of our study was to explore and compare the immunogenicity of SARS-CoV-2 S-, M- and N-proteins in context of different COVID-19 manifestations. Analyzing a cohort of COVID-19 patients with moderate, severe, and critical disease severity, we show that overlapping peptide pools (OPP) of all three proteins can activate SARS-CoV-2-reactive T-cells with a stronger response of CD4+ compared to CD8+ T-cells. Although interindividual variations for the three proteins were observed, M protein induced the highest frequencies of CD4+ T-cells, suggesting its relevance as diagnostic and vaccination target. Importantly, patients with critical COVID-19 demonstrated the strongest T-cell response, including the highest frequencies of cytokine-producing bi- and trifunctional T-cells, for all three proteins. Although the higher magnitude and superior functionality of SARS-CoV-2-reactive T-cells in critical patients can also be a result of a stronger immunogenicity provided by severe infection, it disproves the hypothesis of insufficient SARS-CoV-2-reactive immunity in critical COVID-19. To this end, activation of effector T-cells with differentiated memory phenotype found in our study could cause hyper-reactive response in critical cases leading to immunopathogenesis. Conclusively, since the S-, M-, and N-proteins induce T-cell responses with individual differences, all three proteins should be evaluated for diagnostics and therapeutic strategies to avoid underestimation of cellular immunity and to deepen our understanding of COVID-19 immunity.

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.

Sign in / Sign up

Export Citation Format

Share Document