Longitudinal analysis shows durable and broad immune memory after SARS-CoV-2 infection with persisting antibody responses and memory B and T cells

BackgroundWith the poorest 5-year survival of all cancers, improving treatment for pancreatic cancer is one of the biggest challenges in cancer research. In this era of combination immunotherapies, we sought to explore the potential of combining both priming and activation of the immune system. To achieve this, we combined a CD40 agonist with interleukin-15 and tested its potential in pancreatic cancer.MethodsTwo different mouse models of pancreatic cancer were used to assess the potential of this combination regimen. Therefore, effects on tumour growth kinetics and survival were charted. Differential effects on immune signatures was investigated using RNA sequencing. Functional immune subset involvement was tested using different immune depletion experiments and multicolour flow cytometry in different relevant immune sites. Immune memory was checked using re-challenge experiments.ResultsWe demonstrated profound reduction in tumour growth and increased survival of mice with the majority of mice being cured when both agents were combined, including an unprecedented dose reduction of CD40 agonist without losing any efficacy (fig 1). RNA sequencing analysis showed involvement of natural killer cell and T cell mediated anti-tumour responses and the importance of antigen-presenting cell pathways. This combination resulted in enhanced infiltration of tumours by both cytotoxic T cells and natural killer cells, as well as a striking increase in the ratio of CD8+ T cells over T regulatory cells. We also observed a significant increase in numbers of dendritic cells in tumour draining lymph nodes, particularly CD103+ dendritic cells with cross-presentation potential. A critical role for CD8+ T cells and involvement of natural killer cells in the anti-tumour effect was highlighted. Importantly, strong immune memory was established, with an increase in memory CD8+ T cells only when both interleukin-15 and the CD40 agonist were combined.Abstract 453 Figure 1Tumour kinetics and survival in Panc02 (left) and KPC (right) pancreatic cancer mouse modelsConclusionsWe demonstrated profound synergistic anti-tumour effects upon combination of CD40 agonist and interleukin-15 treatment in mouse models of pancreatic cancer. This preclinical data supports initiation of a first-in-human clinical trial with this combination immunotherapy strategy in pancreatic cancer.

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Heterologous vaccination regimens with self-amplifying RNA and adenoviral COVID vaccines induce robust immune responses in mice

Nature Communications ◽

10.1038/s41467-021-23173-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Alexandra J. Spencer ◽

Paul F. McKay ◽

Sandra Belij-Rammerstorfer ◽

Marta Ulaszewska ◽

Cameron D. Bissett ◽

...

Keyword(s):

Immune Response ◽

Clinical Trials ◽

T Cells ◽

Immune Responses ◽

Viral Vectors ◽

Cytotoxic T Cells ◽

Antibody Responses ◽

Limited Data ◽

Vectored Vaccine ◽

Cellular Immune

AbstractSeveral vaccines have demonstrated efficacy against SARS-CoV-2 mediated disease, yet there is limited data on the immune response induced by heterologous vaccination regimens using alternate vaccine modalities. Here, we present a detailed description of the immune response, in mice, following vaccination with a self-amplifying RNA (saRNA) vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2. We demonstrate that antibody responses are higher in two-dose heterologous vaccination regimens than single-dose regimens. Neutralising titres after heterologous prime-boost were at least comparable or higher than the titres measured after homologous prime boost vaccination with viral vectors. Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1+ CD4 T cells, which is superior to the response induced in homologous vaccination regimens in mice. These results underpin the need for clinical trials to investigate the immunogenicity of heterologous regimens with alternate vaccine technologies.

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Id3 and Bcl6 Promote the Development of Long-Term Immune Memory Induced by Tuberculosis Subunit Vaccine

Vaccines ◽

10.3390/vaccines9020126 ◽

2021 ◽

Vol 9 (2) ◽

pp. 126

Author(s):

Jiangyuan Han ◽

Yanlin Ma ◽

Lan Ma ◽

Daquan Tan ◽

Hongxia Niu ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Subunit Vaccine ◽

Memory T Cells ◽

Transcriptional Factors ◽

Immune Memory ◽

Proliferative Potential ◽

Adeno Associated Virus ◽

Adjuvant Effects

Long-lived memory cell formation and maintenance are usually regulated by cytokines and transcriptional factors. Adjuvant effects of IL-7 have been studied in the vaccines of influenza and other pathogens. However, few studies investigated the adjuvant effects of cytokines and transcriptional factors in prolonging the immune memory induced by a tuberculosis (TB) subunit vaccine. To address this research gap, mice were treated with the Mycobacterium tuberculosis (M. tuberculosis) subunit vaccine Mtb10.4-HspX (MH) plus ESAT6-Ag85B-MPT64<190–198>-Mtb8.4-Rv2626c (LT70), together with adeno-associated virus-mediated IL-7 or lentivirus-mediated transcriptional factor Id3, Bcl6, Bach2, and Blimp1 at 0, 2, and 4 weeks, respectively. Immune responses induced by the vaccine were examined at 25 weeks after last immunization. The results showed that adeno-associated virus-mediated IL-7 allowed the TB subunit vaccine to induce the formation of long-lived memory T cells. Meanwhile, IL-7 increased the expression of Id3, Bcl6, and bach2—the three key transcription factors for the generation of long-lived memory T cells. The adjuvant effects of transcriptional factors, together with TB fusion protein MH/LT70 vaccination, showed that both Bcl6 and Id3 increased the production of antigen-specific antibodies and long-lived memory T cells, characterized by high proliferative potential of antigen-specific CD4+ and CD8+ T cells, and IFN-γ secretion in CD4+ and CD8+ T cells, respectively, after re-exposure to the same antigen. Overall, our study suggests that IL-7 and transcriptional factors Id3 and Bcl6 help the TB subunit vaccine to induce long-term immune memory, which contributes to providing immune protection against M. tuberculosis infection.

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CD4+ CD25+ Regulatory T Cells Modulate the T-Cell and Antibody Responses in Helicobacter-Infected BALB/c Mice

Infection and Immunity ◽

10.1128/iai.01314-05 ◽

2006 ◽

Vol 74 (6) ◽

pp. 3519-3529 ◽

Cited By ~ 41

Author(s):

Maria Kaparakis ◽

Karen L. Laurie ◽

Odilia Wijburg ◽

John Pedersen ◽

Martin Pearse ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Bacterial Colonization ◽

Antibody Responses ◽

T Helper 1 ◽

Time Of Infection ◽

Lymph Node Cells ◽

Antibody Levels ◽

And Control

ABSTRACT Gastric Helicobacter spp. induce chronic gastritis that may lead to ulceration and dysplasia. The host elicits a T helper 1 (Th1) response that is fundamental to the pathogenesis of these bacteria. We analyzed immune responses in Helicobacter-infected, normal mice depleted of CD4+ CD25+ T cells to investigate the in vivo role of regulatory T cells (Tregs) in the modulation of Helicobacter immunopathology. BALB/c and transgenic mice were depleted of CD4+ CD25+ T cells by administration of an anti-CD25 antibody either at the time of infection with Helicobacter or during chronic infection and gastritis. Depletion of CD25+ Tregs prior to and during infection of mice with Helicobacter spp. did not affect either bacterial colonization or severity of gastritis. Depletion of CD25+ Tregs was associated with increased Helicobacter-specific antibody levels and an altered isotype distribution. Paragastric lymph node cells from CD25+ Treg-depleted and control infected mice showed similar proliferation to Helicobacter antigens, but only cells from anti-CD25-treated animals secreted Th2 cytokines. CD25+ Tregs do not control the level of gastritis induced by gastric Helicobacter spp. in normal, thymus-intact BALB/c mice. However, CD25+ Tregs influence the cytokine and antibody responses induced by infection. Autoimmune gastritis is not induced in Helicobacter-infected mice depleted of CD25+ Tregs but is induced in CD25+ Treg-depleted mice, which have a higher frequency of autoreactive T cells.

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Effect of pregnancy specific β1-glycoprotein on the replicative potential of naive T-cells and immune memory T-cells

Bulletin of Experimental Biology and Medicine ◽

10.47056/0365-9615-2021-172-8-198-204 ◽

2021 ◽

Vol 172 (8) ◽

pp. 198-204

Author(s):

V. P. Timganova ◽

◽

L. S. Litvinova ◽

K. A. Yurova ◽

O. G. Khaziakhmatova ◽

...

Keyword(s):

T Cells ◽

Memory T Cells ◽

Immune Memory ◽

Naive T Cells ◽

Naïve T Cells

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The influence of chorionic gonadotropin on phenotype conversion and hTERT gene expression by T-lymphocytes of different degrees of differentiation

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20176306539 ◽

2017 ◽

Vol 63 (6) ◽

pp. 539-545 ◽

Cited By ~ 1

Author(s):

M.B. Rayev ◽

S.A. Zamorina ◽

L.S. Litvinova ◽

K.A. Yurova ◽

O.G. Khaziakhmatova ◽

...

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Chorionic Gonadotropin ◽

Memory T Cells ◽

Immune Memory ◽

Proliferation Marker ◽

Naive T Cells ◽

Naïve T Cells ◽

Htert Gene

The effects of chorionic gonadotropin (hCG) on the expression of the hTERT gene in combination with the conversion of the phenotype of naive T-cells and T-cells of immune memory in vitro were studied. hCG inhibited expression of hTERT mRNA in naive T-cells (CD45RA+) and immune memory T cells (CD45RO+), causing a decrease in the replicative potential of the cells. The presence of hCG in the culture led to the conversion of the phenotype of T-lymphocytes. hCG reduced the number of proliferating T-cells of immune memory, estimated by phenotypic signs by differential gating. hCG (10 IU/ml and 100 IU/ml) inhibited expression of CD25 by the studied populations, but did not modulate expression of the CD71 proliferation marker. Thus, hCG inhibited the functional activity of naive T-cells and T-cells of immune memory, which, in the context of pregnancy, can contribute to the formation of immune tolerance to the semi-allogenic fetus.

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Antigen-specific suppression of human antibody responses by allogeneic T cells II. Cell interactions involved in the generation of suppression

European Journal of Immunology ◽

10.1002/eji.1830160308 ◽

1986 ◽

Vol 16 (3) ◽

pp. 252-256 ◽

Cited By ~ 4

Author(s):

Robin E. Callard ◽

Shane L. Tiernan ◽

Carrie M. Winger

Keyword(s):

T Cells ◽

Cell Interactions ◽

Antibody Responses ◽

Human Antibody ◽

Specific Suppression

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Immunity and Protection – Basic Considerations

10.33442/vt202105 ◽

2021 ◽

Author(s):

Heinz-Josef Schmitt

Keyword(s):

T Cells ◽

Real Life ◽

Booster Vaccination ◽

Immune Memory ◽

Specific Antibodies ◽

Cell Immunity ◽

Time Of Infection ◽

Individual Protection ◽

Functional Antibodies ◽

Almost All

Innate and adaptive immunity generate pathogen-specific antibodies and cells as basis for the efficacy and effectiveness of vaccines: immunity results in protection. For almost all currently licensed vaccines, functional antibodies are the most relevant mechanism of action; they work by binding of an antigen, agglutination, neutralization, complement activation and opsonization directed against specific pathogens or toxins. Immune memory generated by either infection or vaccine priming allows rapid production of antibodies and immune cells (3-7 days) upon later re-infection or (booster-) vaccination. Vaccine-induced immunity may result in protection even in the absence of any measurable specific antibodies at the time of infection – due to memory cells, and due to the effects of T-cells. CD4+ T-cells (“T-helper cells”) induce protection largely by cytokine production, CD8+ T-cells can directly or indirectly kill infected or cancerous cells and they can help clear infections. While antibodies against vaccine antigens can easily be measured by a variety of methods, testing for specific T-cell immunity is less well standardized and more difficult to perform. The term “seroprotection” indicates a serological value (e.g. a titre), associated with protection used for the purpose of vaccine licensure. Measurements of seroprotection can be the percentage of seroresponders, GMTs, fold rise of antibodies or RCD curves. In real life, many factors may contribute to individual protection in both, a positive and a negative direction, including factors inherent with the infecting pathogen, epidemiological factors, host factors, and characteristics of the vaccine and vaccination. Unlike general public belief, the “failure to vaccinate” is more relevant than “vaccine failures” in a population.

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Contact-dependent delivery of IL-2 by dendritic cells to CD4 T cells in the contraction phase promotes their long-term survival

Protein & Cell ◽

10.1007/s13238-019-00662-0 ◽

2019 ◽

Vol 11 (2) ◽

pp. 108-123

Author(s):

Dan Tong ◽

Li Zhang ◽

Fei Ning ◽

Ying Xu ◽

Xiaoyu Hu ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Cd4 T Cell ◽

Immune Memory ◽

Term Survival

Abstract Common γ chain cytokines are important for immune memory formation. Among them, the role of IL-2 remains to be fully explored. It has been suggested that this cytokine is critically needed in the late phase of primary CD4 T cell activation. Lack of IL-2 at this stage sets for a diminished recall response in subsequent challenges. However, as IL-2 peak production is over at this point, the source and the exact mechanism that promotes its production remain elusive. We report here that resting, previously antigen-stimulated CD4 T cells maintain a minimalist response to dendritic cells after their peak activation in vitro. This subtle activation event may be induced by DCs without overt presence of antigen and appears to be stronger if IL-2 comes from the same dendritic cells. This encounter reactivates a miniature IL-2 production and leads a gene expression profile change in these previously activated CD4 T cells. The CD4 T cells so experienced show enhanced reactivation intensity upon secondary challenges later on. Although mostly relying on in vitro evidence, our work may implicate a subtle programing for CD4 T cell survival after primary activation in vivo.

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