Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance

Current treatments to control pathological or unwanted immune responses often use broadly immunosuppressive drugs. New approaches to induce antigen-specific immunological tolerance that control both cellular and humoral immune responses are desirable. Here we describe the use of synthetic, biodegradable nanoparticles carrying either protein or peptide antigens and a tolerogenic immunomodulator, rapamycin, to induce durable and antigen-specific immune tolerance, even in the presence of potent Toll-like receptor agonists. Treatment with tolerogenic nanoparticles results in the inhibition of CD4+ and CD8+ T-cell activation, an increase in regulatory cells, durable B-cell tolerance resistant to multiple immunogenic challenges, and the inhibition of antigen-specific hypersensitivity reactions, relapsing experimental autoimmune encephalomyelitis, and antibody responses against coagulation factor VIII in hemophilia A mice, even in animals previously sensitized to antigen. Only encapsulated rapamycin, not the free form, could induce immunological tolerance. Tolerogenic nanoparticle therapy represents a potential novel approach for the treatment of allergies, autoimmune diseases, and prevention of antidrug antibodies against biologic therapies.

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Cellular and humoral immune responses associated with protection in sheep vaccinated against Teladorsagia circumcincta

Veterinary Research ◽

10.1186/s13567-021-00960-8 ◽

2021 ◽

Vol 52 (1) ◽

Author(s):

Cynthia Machín ◽

Yolanda Corripio-Miyar ◽

Julia N. Hernández ◽

Tara Pérez-Hernández ◽

Adam D. Hayward ◽

...

Keyword(s):

Immune Responses ◽

T Cell Activation ◽

Cell Activation ◽

Anthelmintic Resistance ◽

Gastrointestinal Nematodes ◽

Control Group ◽

Sheep Breeds ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Teladorsagia Circumcincta

AbstractDue to increased anthelmintic resistance, complementary methods to drugs are necessary to control gastrointestinal nematodes (GIN). Vaccines are an environmentally-friendly and promising option. In a previous study, a Teladorsagia circumcincta recombinant sub-unit vaccine was administered to two sheep breeds with different levels of resistance against GIN. In the susceptible Canaria Sheep (CS) breed, vaccinates harboured smaller worms with fewer eggs in utero than the control group. Here, we extend this work, by investigating the cellular and humoral immune responses of these two sheep breeds following vaccination and experimental infection with T. circumcincta. In the vaccinated CS group, negative associations between antigen-specific IgA, IgG2 and Globule Leukocytes (GLs) with several parasitological parameters were established as well as a higher CD4+/CD8+ ratio than in control CS animals, suggesting a key role in the protection induced by the vaccine. In the more resistant Canaria Hair Breed (CHB) sheep the vaccine did not significantly impact on the parasitological parameters studied and none of these humoral associations were observed in vaccinated CHB lambs, although CHB had higher proportions of CD4+ and CD8+ T cells within the abomasal lymph nodes, suggesting higher mucosal T cell activation. Each of the component proteins in the vaccine induced an increase in immunoglobulin levels in vaccinated groups of each breed. However, levels of immunoglobulins to only three of the antigens (Tci-MEP-1, Tci-SAA-1, Tci-ASP-1) were negatively correlated with parasitological parameters in the CS breed and they may be, at least partially, responsible for the protective effect of the vaccine in this breed. These data could be useful for improving the current vaccine prototype.

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Characteristics of immune response to protozoan infections

Medicinski pregled ◽

10.2298/mpns0312557a ◽

2003 ◽

Vol 56 (11-12) ◽

pp. 557-563 ◽

Cited By ~ 3

Author(s):

Valentina Arsic-Arsenijevic ◽

Aleksandar Dzamic ◽

Sanja Mitrovic ◽

Ivana Radonjic ◽

Ivana Kranjcic-Zec

Keyword(s):

Immune Response ◽

Immune Responses ◽

T Cell Activation ◽

Defense Mechanisms ◽

Cell Activation ◽

Blood Stream ◽

Biochemical Properties ◽

Natural Immunity ◽

Humoral Immune ◽

Specific Immunity

Introduction When protozoa enter the blood stream or tissues they can often survive and replicate because they adapt to the resisting natural host defenses. The interaction of immune system with infectious organisms is a dynamic interplay of host mechanisms aimed at eliminating infections and microbial strategies designed to permit survival in the face of powerful effectors mechanisms. Protozoa cause chronic and persistent infections, because natural immunity against them is weak and because protozoa have evolved multiple mechanisms for evading and resisting specific immunity. Natural and specific immune response to protozoa Different protozoa vary greatly in their structural and biochemical properties and stimulate distinct patterns of immune responses and have evolved unique mechanisms for evading specific immunity. Protozoa activate quite distinct specific immune responses, which are different from the responses to fungi, bacteria and viruses. Protozoa may be phagocytozed by macrophages, but many are resistant to phagocytic killing and may even replicate within macrophages. T. brucei gambiense is the best example of protozoa which can induce humoral immune response because of its extra-cellular location. In Leishmania sp. infections, cellular defense mechanisms depend upon CD4+ T-lymphocytes and activate macrophages as effectors cells that are regulated by cytokines of Th1 subset. Plasmodium sp. is a protozoa which show the diversity of defence mechanisms which can be cellular or humoral, depending on Ag and protozoa's location. Immune evasion mechanisms of protozoa Different protozoa have developed remarkably effective ways of resisting specific immunity: a) anatomic sequestration is commonly observed with protozoa Plasmodium and T. gondii; b) some protozoa can become resistant to immune effectors mechanisms: Trypanosoma, Leishmania and T. gondii; c) some protozoa have developed effective mechanisms for varying their surface antigens: Plasmodium and Trypanosoma; d) some protozoa shed their antigen coats, either spontaneously or after binding with specific antibodies: E. histolytica; e) some protozoa alter host immune response by nonspecific and generalized immunosuppression (abnormalities in cytokine production, deficient T cell activation): Trypanosoma, Leishmania, Toxoplasma, Entamoeba. Conclusion Protozoa activate numerous, different immune mechanisms in human body. Evolution, progression and outcome of diseases depend upon these mechanisms. Resent progresses in research have defined and selected Ag as candidates for new vaccines. Better definitions regarding the role of cytokines in protozoaninfections will facilitate rational development of cytokines and cytokine antagonists and their use as immunotherapeutic agents.

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Interdependencies between cellular and humoral immune responses in heterologous and homologous SARS-CoV-2 vaccination

10.1101/2021.12.13.21267729 ◽

2021 ◽

Author(s):

Moritz M Hollstein ◽

Lennart Muensterkoetter ◽

Michael P Schoen ◽

Armin Bergmann ◽

Thea M Husar ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

T Cell Activation ◽

Neutralizing Antibodies ◽

Cell Activation ◽

Booster Vaccination ◽

Antibody Avidity ◽

Humoral Immune ◽

Cellular Immune Responses ◽

Cellular Immune

Background: Homologous and heterologous SARS-CoV-2-vaccinations yield different spike protein-directed humoral and cellular immune responses. However, their interdependencies remain elusive. Methods: COV-ADAPT is a prospective, observational cohort study of 417 healthcare workers who received homologous vaccination with Astra (ChAdOx1-S; AstraZeneca) or BNT (BNT162b2; Biontech/Pfizer) or heterologous vaccination with Astra/BNT. We assessed the humoral (anti-spike-RBD-IgG, neutralizing antibodies, antibody avidity) and cellular (spike-induced T cell interferon-y release) immune response in blood samples up to 2 weeks before (T1) and 2 to 12 weeks following secondary immunization (T2). Findings: Initial vaccination with Astra resulted in lower anti-spike-RBD-IgG responses compared to BNT (70+/-114 vs. 226+/-279 BAU/ml, p<0.01) at T1, whereas T cell activation did not differ significantly. Booster vaccination with BNT proved superior to Astra at T2 (anti-spike-RBD-IgG: Astra/BNT 2387+/-1627 and BNT/BNT 3202+/-2184 vs. Astra/Astra 413+/-461 BAU/ml, both p<0.001; spike-induced T cell interferon-y; release: Astra/BNT 5069+/-6733 and BNT/BNT 4880+/-7570 vs. Astra/Astra 1152+/-2243 mIU/ml, both p<0.001). No significant differences were detected between BNT-boostered groups at T2. For Astra, we observed no booster effect on T cell activation. We found associations between anti-spike-RBD-IgG levels (Astra/BNT and BNT/BNT) and T cell responses (Astra/Astra and Astra/BNT) from T1 to T2. There were also links between levels of anti-spike-RBD-IgG and T cell at both time points (all groups combined). All regimes yielded neutralizing antibodies and increased antibody avidity at T2. Interpretation: Interdependencies between humoral and cellular immune responses differ between common SARS-CoV-2 vaccination regimes. T cell activation is unlikely to compensate for poor humoral responses. Funding: Deutsche Forschungsgemeinschaft (DFG), ER723/3-1

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Antigen targeting to splenic CD169+ macrophages induces strong humoral immune responses and CD4+ T cell activation

Molecular Immunology ◽

10.1016/j.molimm.2012.02.030 ◽

2012 ◽

Vol 51 (1) ◽

pp. 12-13

Author(s):

Henrike Veninga ◽

Ellen Borg ◽

Hakan Kalay ◽

Yvette van Kooyk ◽

Georg Kraal ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

T Cell Activation ◽

Cell Activation ◽

Cd4 T Cell ◽

Humoral Immune ◽

Humoral Immune Responses

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Notch2-dependent DC2s mediate splenic germinal center responses

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1809925115 ◽

2018 ◽

Vol 115 (42) ◽

pp. 10726-10731 ◽

Cited By ~ 23

Author(s):

Carlos G. Briseño ◽

Ansuman T. Satpathy ◽

Jesse T. Davidson ◽

Stephen T. Ferris ◽

Vivek Durai ◽

...

Keyword(s):

Immune Responses ◽

Mhc Class Ii ◽

T Cell Activation ◽

Humoral Immunity ◽

Germinal Center ◽

Cell Activation ◽

Cell Formation ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Follicular Helper

CD4+ T follicular helper (TFH) cells support germinal center (GC) reactions promoting humoral immunity. Dendritic cell (DC) diversification into genetically distinct subsets allows for specialization in promoting responses against several types of pathogens. Whether any classical DC (cDC) subset is required for humoral immunity is unknown, however. We tested several genetic models that selectively ablate distinct DC subsets in mice for their impact on splenic GC reactions. We identified a requirement for Notch2-dependent cDC2s, but not Batf3-dependent cDC1s or Klf4-dependent cDC2s, in promoting TFH and GC B cell formation in response to sheep red blood cells and inactivated Listeria monocytogenes. This effect was mediated independent of Il2ra and several Notch2-dependent genes expressed in cDC2s, including Stat4 and Havcr2. Notch2 signaling during cDC2 development also substantially reduced the efficiency of cDC2s for presentation of MHC class II-restricted antigens, limiting the strength of CD4 T cell activation. Together, these results demonstrate a nonredundant role for the Notch2-dependent cDC2 subset in supporting humoral immune responses.

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Differences in TCR repertoire and T cell activation underlie the divergent outcomes of antitumor immune responses in tumor-eradicating versus tumor-progressing hosts

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001615 ◽

2021 ◽

Vol 9 (1) ◽

pp. e001615

Author(s):

Rachel A Woolaver ◽

Xiaoguang Wang ◽

Alexandra L Krinsky ◽

Brittany C Waschke ◽

Samantha M Y Chen ◽

...

Keyword(s):

T Cell ◽

Mouse Model ◽

Immune Responses ◽

Single Cell ◽

T Cell Activation ◽

Antitumor Immunity ◽

Cell Activation ◽

Tcr Repertoire ◽

Underlying Mechanisms ◽

Personalized Cancer

BackgroundAntitumor immunity is highly heterogeneous between individuals; however, underlying mechanisms remain elusive, despite their potential to improve personalized cancer immunotherapy. Head and neck squamous cell carcinomas (HNSCCs) vary significantly in immune infiltration and therapeutic responses between patients, demanding a mouse model with appropriate heterogeneity to investigate mechanistic differences.MethodsWe developed a unique HNSCC mouse model to investigate underlying mechanisms of heterogeneous antitumor immunity. This model system may provide a better control for tumor-intrinsic and host-genetic variables, thereby uncovering the contribution of the adaptive immunity to tumor eradication. We employed single-cell T-cell receptor (TCR) sequencing coupled with single-cell RNA sequencing to identify the difference in TCR repertoire of CD8 tumor-infiltrating lymphocytes (TILs) and the unique activation states linked with different TCR clonotypes.ResultsWe discovered that genetically identical wild-type recipient mice responded heterogeneously to the same squamous cell carcinoma tumors orthotopically transplanted into the buccal mucosa. While tumors initially grew in 100% of recipients and most developed aggressive tumors, ~25% of recipients reproducibly eradicated tumors without intervention. Heterogeneous antitumor responses were dependent on CD8 T cells. Consistently, CD8 TILs in regressing tumors were significantly increased and more activated. Single-cell TCR-sequencing revealed that CD8 TILs from both growing and regressing tumors displayed evidence of clonal expansion compared with splenic controls. However, top TCR clonotypes and TCR specificity groups appear to be mutually exclusive between regressing and growing TILs. Furthermore, many TCRα/TCRβ sequences only occur in one recipient. By coupling single-cell transcriptomic analysis with unique TCR clonotypes, we found that top TCR clonotypes clustered in distinct activation states in regressing versus growing TILs. Intriguingly, the few TCR clonotypes shared between regressors and progressors differed greatly in their activation states, suggesting a more dominant influence from tumor microenvironment than TCR itself on T cell activation status.ConclusionsWe reveal that intrinsic differences in the TCR repertoire of TILs and their different transcriptional trajectories may underlie the heterogeneous antitumor immune responses in different hosts. We suggest that antitumor immune responses are highly individualized and different hosts employ different TCR specificities against the same tumors, which may have important implications for developing personalized cancer immunotherapy.

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Immune Restoration Diseases Reflect Diverse Immunopathological Mechanisms

Clinical Microbiology Reviews ◽

10.1128/cmr.00015-09 ◽

2009 ◽

Vol 22 (4) ◽

pp. 651-663 ◽

Cited By ~ 45

Author(s):

Patricia Price ◽

David M. Murdoch ◽

Upasna Agarwal ◽

Sharon R. Lewin ◽

Julian H. Elliott ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

T Cell Activation ◽

Cell Activation ◽

De Novo ◽

Granulomatous Inflammation ◽

T Cell Response ◽

Immune Restoration ◽

Immunological Parameters ◽

Varicella Zoster

SUMMARY Up to one in four patients infected with human immunodeficiency virus type 1 and given antiretroviral therapy (ART) experiences inflammatory or cellular proliferative disease associated with a preexisting opportunistic infection, which may be subclinical. These immune restoration diseases (IRD) appear to result from the restoration of immunocompetence. IRD associated with intracellular pathogens are characterized by cellular immune responses and/or granulomatous inflammation. Mycobacterial and cryptococcal IRD are attributed to a pathological overproduction of Th1 cytokines. Clinicopathological characteristics of IRD associated with viral infections suggest different pathogenic mechanisms. For example, IRD associated with varicella-zoster virus or JC polyomavirus infection correlate with a CD8 T-cell response in the central nervous system. Exacerbations or de novo presentations of hepatitis associated with hepatitis C virus (HCV) infection following ART may also reflect restoration of pathogen-specific immune responses as titers of HCV-reactive antibodies rise in parallel with liver enzymes and plasma markers of T-cell activation. Correlations between immunological parameters assessed in longitudinal sample sets and clinical presentations are required to illuminate the diverse immunological scenarios described collectively as IRD. Here we present salient clinical features and review progress toward understanding their pathogeneses.

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A role for CD9 molecules in T cell activation.

Journal of Experimental Medicine ◽

10.1084/jem.184.2.753 ◽

1996 ◽

Vol 184 (2) ◽

pp. 753-758 ◽

Cited By ~ 63

Author(s):

X G Tai ◽

Y Yashiro ◽

R Abe ◽

K Toyooka ◽

C R Wood ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

T Cell Activation ◽

Cell Activation ◽

Expression Cloning ◽

Wild Type ◽

Almost All ◽

Antigen Presenting ◽

Deficient Mice

Costimulation mediated by the CD28 molecule plays an important role in optimal activation of T cells. However, CD28-deficient mice can mount effective T cell-dependent immune responses, suggesting the existence of other costimulatory systems. In a search for other costimulatory molecules on T cells, we have developed a monoclonal antibody (mAb) that can costimulate T cells in the absence of antigen-presenting cells (APC). The molecule recognized by this mAb, 9D3, was found to be expressed on almost all mature T cells and to be a protein of approximately 24 kD molecular mass. By expression cloning, this molecule was identified as CD9, 9D3 (anti-CD9) synergized with suboptimal doses of anti-CD3 mAb in inducing proliferation by virgin T cells. Costimulation was induced by independent ligation of CD3 and CD9, suggesting that colocalization of these two molecules is not required for T cell activation. The costimulation by anti-CD9 was as potent as that by anti-CD28. Moreover, anti-CD9 costimulated in a CD28-independent way because anti-CD9 equally costimulated T cells from the CD28-deficient as well as wild-type mice. Thus, these results indicate that CD9 serves as a molecule on T cells that can deliver a potent CD28-independent costimulatory signal.

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NFAT control of immune function: New Frontiers for an Abiding Trooper

F1000Research ◽

10.12688/f1000research.13426.1 ◽

2018 ◽

Vol 7 ◽

pp. 260 ◽

Cited By ~ 38

Author(s):

Martin Vaeth ◽

Stefan Feske

Keyword(s):

T Cells ◽

Transcription Factor ◽

Immune Responses ◽

Physiological Function ◽

Large Body ◽

Immunological Tolerance ◽

Nuclear Factor ◽

Activated T Cells ◽

Humoral Immune ◽

Humoral Immune Responses

Nuclear factor of activated T cells (NFAT) was first described almost three decades ago as a Ca2+/calcineurin-regulated transcription factor in T cells. Since then, a large body of research uncovered the regulation and physiological function of different NFAT homologues in the immune system and many other tissues. In this review, we will discuss novel roles of NFAT in T cells, focusing mainly on its function in humoral immune responses, immunological tolerance, and the regulation of immune metabolism.

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