scholarly journals Positive and Negative Regulation of Cellular Immune Responses in Physiologic Conditions and Diseases

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
S. Viganò ◽  
M. Perreau ◽  
G. Pantaleo ◽  
A. Harari
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Immune Responses ◽  
Viral Infections ◽  
Therapeutic Interventions ◽  
Cellular Immune

The immune system has evolved to allow robust responses against pathogens while avoiding autoimmunity. This is notably enabled by stimulatory and inhibitory signals which contribute to the regulation of immune responses. In the presence of a pathogen, a specific and effective immune response must be induced and this leads to antigen-specific T-cell proliferation, cytokines production, and induction of T-cell differentiation toward an effector phenotype. After clearance or control of the pathogen, the effector immune response must be terminated in order to avoid tissue damage and chronic inflammation and this process involves coinhibitory molecules. When the immune system fails to eliminate or control the pathogen, continuous stimulation of T cells prevents the full contraction and leads to the functional exhaustion of effector T cells. Several evidences bothin vitroandin vivosuggest that this anergic state can be reverted by blocking the interactions between coinhibitory molecules and their ligands. The potential to revert exhausted or inactivated T-cell responses following selective blocking of their function made these markers interesting targets for therapeutic interventions in patients with persistent viral infections or cancer.

C5a Complement Depletion Suppresses In Vivo B Lymphoma Progression and Enhances Development Of Cellular Anti-Tumor Immune Response

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1837-1837
Author(s):  
Suresh Veeramani ◽  
George J. Weiner
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Cd8 T Cells ◽  
B Lymphoma

Abstract Background Proteins within the complement system have complex effects on cellular immune responses. In previous studies, we found that active complement components, especially C5a, can dampen the development of antigen-specific immune responses following vaccination with a model antigen, in part by promoting generation of APC-induced T regulatory (Treg) cells. These studies also demonstrated that B lymphoma cell lines exposed to complement can induce Treg generation in vitro. The current study was designed to address whether depletion of C5a could enhance development of a cellular anti-lymphoma immune response in vivo. Methods Immunocompetent Balb/C mice were inoculated subcutaneously with syngeneic A20 B lymphoma cells mixed with either 10 μg of rat anti-mouse C5a monoclonal antibody (mAb) or 10 μg of isotype-matched Rat IgG2a control mAb. Tumor growth was followed. In select experiments, mice were sacrificed and analyzed for the percentage and activity of tumor-infiltrating T cells and A20-specific splenic T cell responses. Results 1. Tumor progression. Lymphoma grew more slowly in mice treated with anti-C5a mAb compared to mice treated with control mAb (p<0.05) {Fig. 1). 2. Intratumoral T cells. Tumors from mice treated with anti-C5a mAb had higher CD8+ T cell infiltration compared to mice treated with control mAb (p=0.002) (Fig. 2). Tumor-infiltrating CD8+ T cells showed a trend towards higher intracellular IFNg production in mice treated with anti-C5a mAb compared to control mAb (p=0.051). 3. Splenic T cells. Splenic T cells from mice treated with anti-C5a mAb produced IFNg to a greater degree than did splenic T cells from control mice when splenocytes were cultured with irradiated A20 cells in vitro (p=0.041) (Fig. 3). There was a trend towards decreased numbers of splenic CD4+CD25highFoxp3+ Tregs in C5a-depleted mice compared to control mice. Conclusions Depletion of C5a at the site of tumor inoculation slows tumor growth and increases the number of tumor infiltrating CD8 T cells in a syngenic immunocompetent model of lymphoma. A trend towards enhanced production of IFNg in the tumor infiltrating T cells, increased numbers of tumor-specific splenic T cells, and reduced numbers of splenic Tregs, suggests intratumoral C5a depletion can enhance tumor-specific immune responses both within the tumor and systemically. Ongoing studies are exploring the molecular mechanisms involved in C5a-promoted tumor progression and the use of C5a depletion as a novel strategy to improve anti-tumor immunity. Disclosures: No relevant conflicts of interest to declare.

A glimpse into the diverse cellular immunity against SARS-CoV-2

2021 ◽  
Author(s):  
Cheng-Wei Chang ◽  
Yuchen Liu ◽  
Cheng Jiao ◽  
Hongwei Liu ◽  
Xiaochuan Chen ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Antibody Response ◽  
Cellular Immunity ◽  
Viral Antigens ◽  
Cellular Immune

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific cellular immune response may prove to be essential for long-term immune protection against the novel coronavirus disease 2019 (COVID-19). To assess COVID-19-specific immunity in the population, we synthesized selected peptide pools of SARS-CoV-2 structural and functional proteins, including Spike (S), Membrane (M), Envelope (E), Nucleocapsid (N) and Protease (P) as target antigens. Survey of the T cell precursur frequencies in healthy individuals specific to these viral antigens demonstrated a diverse cellular immunity, including high, medium, low and no responders. This was further confirmed by in vitro induction of anti-SARS-CoV-2 T cell immune responses using dendritic cell (DC)/T cell coculture, which supported the corresponding T cell precursor frequencies in each of the individuals tested. In general, the combination of all five viral antigen pools induced the strongest cellular immune response, yet individual donors responded differently to different viral antigens. Importantly, in vitro restimulation of the T cells with the DC-peptides induced increased anti-viral immune responses in all individuals even in the no responders, suggesting that repeated antigen stimulation could elicit a broad protection in immune naïve population. Our analysis recapitulates the critical role of cellular immunity in fighting COVID-19 and the importance of analyzing anti-SARS-CoV-2 T cell response in addition to antibody response in the population.ImportanceFacing the rapid evolving SARS-CoV-2 variants in the world, current emphasis on antibody-producing vaccines needs a quick revisit. The virus-specific cellular immunity may prove to be essential for long-term protection against COVID-19. This study designed a series of antigenic peptides encompassing the conserved and/or essential domains of Spike (S), Membrane (M), envelope (E), Nucleocapsid (N) and Protease (P) as targets to assess Covid-19-specific immunity in the population. The results demonstrated a diverse cellular immunity, including high, medium, low and no responders. This was verified by in vitro generation of anti-SARS-CoV-2 T-cells from these subjects. The study suggested that individuals responded differently to the different viral antigens, and importantly, repeated stimulation could produce virus specific T cells in all individuals, including the no responders. This study illustrates the needs for assessing anti-viral cellular immunity in addition to antibody response in the general population.

scholarly journals Optimized Adenovirus-Antibody Complexes Stimulate Strong Cellular and Humoral Immune Responses against an Encoded Antigen in Naïve Mice and Those with Preexisting Immunity

2011 ◽  
Vol 19 (1) ◽  
pp. 84-95 ◽  
Author(s):  
Jin Huk Choi ◽  
Joe Dekker ◽  
Stephen C. Schafer ◽  
Jobby John ◽  
Craig E. Whitfill ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
T Cell Responses ◽  
Transduction Efficiency ◽  
Virus Antibody ◽  
Cell Responses

ABSTRACTThe immune response to recombinant adenoviruses is the most significant impediment to their clinical use for immunization. We test the hypothesis that specific virus-antibody combinations dictate the type of immune response generated against the adenovirus and its transgene cassette under certain physiological conditions while minimizing vector-induced toxicity.In vitroandin vivoassays were used to characterize the transduction efficiency, the T and B cell responses to the encoded transgene, and the toxicity of 1 × 1011adenovirus particles mixed with different concentrations of neutralizing antibodies. Complexes formed at concentrations of 500 to 0.05 times the 50% neutralizing dose (ND50) elicited strong virus- and transgene-specific T cell responses. The 0.05-ND50formulation elicited measurable anti-transgene antibodies that were similar to those of virus alone (P= 0.07). This preparation also elicited very strong transgene-specific memory T cell responses (28.6 ± 5.2% proliferation versus 7.7 ± 1.4% for virus alone). Preexisting immunity significantly reduced all responses elicited by these formulations. Although lower concentrations (0.005 and 0.0005 ND50) of antibody did not improve cellular and humoral responses in naïve animals, they did promote strong cellular (0.005 ND50) and humoral (0.0005 ND50) responses in mice with preexisting immunity. Some virus-antibody complexes may improve the potency of adenovirus-based vaccines in naïve individuals, while others can sway the immune response in those with preexisting immunity. Additional studies with these and other virus-antibody ratios may be useful to predict and model the type of immune responses generated against a transgene in those with different levels of exposure to adenovirus.

scholarly journals GENETIC CONTROL OF IMMUNE RESPONSES IN VITRO

1974 ◽  
Vol 140 (3) ◽  
pp. 648-659 ◽  
Author(s):  
Judith A. Kapp ◽  
Carl W. Pierce ◽  
Stuart Schlossman ◽  
Baruj Benacerraf
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Cell Function ◽  
Suppressor Cells ◽  
Specific Response ◽  
Spleen Cells ◽  
X Irradiation

In recent studies we have found that GAT not only fails to elicit a GAT-specific response in nonresponder mice but also specifically decreases the ability of nonresponder mice to develop a GAT-specific PFC response to a subsequent challenge with GAT bound to the immunogenic carrier, MBSA. Studies presented in this paper demonstrate that B cells from nonresponder, DBA/1 mice rendered unresponsive by GAT in vivo can respond in vitro to GAT-MBSA if exogenous, carrier-primed T cells are added to the cultures. The unresponsiveness was shown to be the result of impaired carrier-specific helper T-cell function in the spleen cells of GAT-primed mice. Spleen cells from GAT-primed mice specifically suppressed the GAT-specific PFC response of spleen cells from normal DBA/1 mice incubated with GAT-MBSA. This suppression was prevented by pretreatment of GAT-primed spleen cells with anti-θ serum plus C or X irradiation. Identification of the suppressor cells as T cells was confirmed by the demonstration that suppressor cells were confined to the fraction of the column-purified lymphocytes which contained θ-positive cells and a few non-Ig-bearing cells. The significance of these data to our understanding of Ir-gene regulation of the immune response is discussed.

T cell-T cell activation in multiple sclerosis

1997 ◽  
Vol 3 (4) ◽  
pp. 238-242 ◽  
Author(s):  
JW Lindsey ◽  
RH Kerman ◽  
JS Wolinsky
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Viral Infections ◽  
Activated T Cells ◽  
In Vitro Proliferation

Activated T cells are able to stimulate proliferation in resting T cells through an antigen non-specific mechanism. The in vivo usefulness of this T cell-T cell activation is unclear, but it may serve to amplify immune responses. T cell-T cell activation could be involved in the well-documented occurrence of multiple sclerosis (MS) exacerbations following viral infections. Excessive activation via this pathway could also be a factor in the etiology of MS. We tested the hypothesis that excessive T cell-T cell activation occurs in MS patients using in vitro proliferation assays comparing T cells from MS patients to T cells from controls. When tested as responder cells, T cells from MS patients proliferated slightly less after stimulation with previously activated cells than T cells from controls. When tested as stimulator cells, activated cells from MS patients stimulated slightly more non-specific proliferation than activated cells from controls. Neither of these differences were statistically significant We conclude that T cell proliferation in response to activated T cells is similar in MS and controls.

scholarly journals Real-time analysis of T cell receptors in naive cells in vitro and in vivo reveals flexibility in synapse and signaling dynamics

2010 ◽  
Vol 207 (12) ◽  
pp. 2733-2749 ◽  
Author(s):  
Rachel S. Friedman ◽  
Peter Beemiller ◽  
Caitlin M. Sorensen ◽  
Jordan Jacobelli ◽  
Matthew F. Krummel
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Real Time ◽  
T Cell Activation ◽  
Valuable Insight ◽  
Time Dynamics ◽  
Insight Into

The real-time dynamics of the T cell receptor (TCR) reflect antigen detection and T cell signaling, providing valuable insight into the evolving events of the immune response. Despite considerable advances in studying TCR dynamics in simplified systems in vitro, live imaging of subcellular signaling complexes expressed at physiological densities in intact tissues has been challenging. In this study, we generated a transgenic mouse with a TCR fused to green fluorescent protein to provide insight into the early signaling events of the immune response. To enable imaging of TCR dynamics in naive T cells in the lymph node, we enhanced signal detection of the fluorescent TCR fusion protein and used volumetric masking with a second fluorophore to mark the T cells expressing the fluorescent TCR. These in vivo analyses and parallel experiments in vitro show minimal and transient incorporation of TCRs into a stable central supramolecular activating cluster (cSMAC) structure but strong evidence for rapid, antigen-dependent TCR internalization that was not contingent on T cell motility arrest or cSMAC formation. Short-lived antigen-independent TCR clustering was also occasionally observed. These in vivo observations demonstrate that varied TCR trafficking and cell arrest dynamics occur during early T cell activation.

scholarly journals Bridging channel dendritic cells induce immunity to transfused red blood cells

2016 ◽  
Vol 213 (6) ◽  
pp. 887-896 ◽  
Author(s):  
Samuele Calabro ◽  
Antonia Gallman ◽  
Uthaman Gowthaman ◽  
Dong Liu ◽  
Pei Chen ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Major Complication ◽  
Life Saving ◽  
T Cell Help ◽  
Rbc Transfusion

Red blood cell (RBC) transfusion is a life-saving therapeutic tool. However, a major complication in transfusion recipients is the generation of antibodies against non-ABO alloantigens on donor RBCs, potentially resulting in hemolysis and renal failure. Long-lived antibody responses typically require CD4+ T cell help and, in murine transfusion models, alloimmunization requires a spleen. Yet, it is not known how RBC-derived antigens are presented to naive T cells in the spleen. We sought to answer whether splenic dendritic cells (DCs) were essential for T cell priming to RBC alloantigens. Transient deletion of conventional DCs at the time of transfusion or splenic DC preactivation before RBC transfusion abrogated T and B cell responses to allogeneic RBCs, even though transfused RBCs persisted in the circulation for weeks. Although all splenic DCs phagocytosed RBCs and activated RBC-specific CD4+ T cells in vitro, only bridging channel 33D1+ DCs were required for alloimmunization in vivo. In contrast, deletion of XCR1+CD8+ DCs did not alter the immune response to RBCs. Our work suggests that blocking the function of one DC subset during a narrow window of time during RBC transfusion could potentially prevent the detrimental immune response that occurs in patients who require lifelong RBC transfusion support.

scholarly journals New differentiation pathway for double-negative regulatory T cells that regulates the magnitude of immune responses

Blood ◽  
2006 ◽  
Vol 109 (9) ◽  
pp. 4071-4079 ◽  
Author(s):  
Dong Zhang ◽  
Wei Yang ◽  
Nicolas Degauque ◽  
Yan Tian ◽  
Allison Mikita ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Surface ◽  
Immune Responses ◽  
Lymphoid Tissues ◽  
Double Negative ◽  
Healthy Humans

Abstract Recent studies have demonstrated that in peripheral lymphoid tissues of normal mice and healthy humans, 1% to 5% of αβ T-cell receptor–positive (TCR+) T cells are CD4−CD8− (double-negative [DN]) T cells, capable of down-regulating immune responses. However, the origin and developmental pathway of DN T cells is still not clear. In this study, by monitoring CD4 expression during T-cell proliferation and differentiation, we identified a new differentiation pathway for the conversion of CD4+ T cells to DN regulatory T cells. We showed that the converted DN T cells retained a stable phenotype after restimulation and that furthermore, the disappearance of cell-surface CD4 molecules on converted DN T cells was a result of CD4 gene silencing. The converted DN T cells were resistant to activation-induced cell death (AICD) and expressed a unique set of cell-surface markers and gene profiles. These cells were highly potent in suppressing alloimmune responses both in vitro and in vivo in an antigen-specific manner. Perforin was highly expressed by the converted DN regulatory T cells and played a role in DN T-cell–mediated suppression. Our findings thus identify a new differentiation pathway for DN regulatory T cells and uncover a new intrinsic homeostatic mechanism that regulates the magnitude of immune responses. This pathway provides a novel, cell-based, therapeutic approach for preventing allograft rejection.

scholarly journals Vaccination with a T-cell-priming Gag peptide of caprine arthritis encephalitis virus enhances virus replication transiently in vivo

2007 ◽  
Vol 88 (5) ◽  
pp. 1589-1593 ◽  
Author(s):  
Chiara Nenci ◽  
Marie-Luise Zahno ◽  
Hans-Rudolf Vogt ◽  
Gabriela Obexer-Ruff ◽  
Marcus G. Doherr ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Virus Replication ◽  
Viral Infections ◽  
Cell Epitope ◽  
Encephalitis Virus ◽  
Interleukin 4 ◽  
Caprine Arthritis Encephalitis Virus

CD4+ T cells are involved in several immune response pathways used to control viral infections. In this study, a group of genetically defined goats was immunized with a synthetic peptide known to encompass an immunodominant helper T-cell epitope of caprine arthritis encephalitis virus (CAEV). Fifty-five days after challenge with the molecularly cloned CAEV strain CO, the vaccinated animals had a higher proviral load than the controls. The measurement of gamma interferon and interleukin-4 gene expression showed that these cytokines were reliable markers of an ongoing immune response but their balance did not account for more or less efficient control of CAEV replication. In contrast, granulocyte–macrophage colony-stimulating factor appeared to be a key cytokine that might support virus replication in the early phase of infection. The observation of a potential T-cell-mediated enhancement of virus replication supports other recent findings showing that lentivirus-specific T cells can be detrimental to the host, suggesting caution in designing vaccine candidates.

scholarly journals Anti-CD40 Antibody Fused to CD40 Ligand Is a Superagonist Platform for Adjuvant Intrinsic DC-Targeting Vaccines

2022 ◽  
Vol 12 ◽  
Author(s):  
Valentina Ceglia ◽  
Sandra Zurawski ◽  
Monica Montes ◽  
Mitchell Kroll ◽  
Aurélie Bouteau ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Class I ◽  
Agonist Activity ◽  
Cell Immunity ◽  
Hiv 1

CD40 is a potent activating receptor expressed on antigen-presenting cells (APCs) of the immune system. CD40 regulates many aspects of B and T cell immunity via interaction with CD40L expressed on activated T cells. Targeting antigens to CD40 via agonistic anti-CD40 antibody fusions promotes both humoral and cellular immunity, but current anti-CD40 antibody-antigen vaccine prototypes require co-adjuvant administration for significant in vivo efficacy. This may be a consequence of dulling of anti-CD40 agonist activity via antigen fusion. We previously demonstrated that direct fusion of CD40L to anti-CD40 antibodies confers superagonist properties. Here we show that anti-CD40-CD40L-antigen fusion constructs retain strong agonist activity, particularly for activation of dendritic cells (DCs). Therefore, we tested anti-CD40-CD40L antibody fused to antigens for eliciting immune responses in vitro and in vivo. In PBMC cultures from HIV-1-infected donors, anti-CD40-CD40L fused to HIV-1 antigens preferentially expanded HIV-1-specific CD8+ T cells versus CD4+ T cells compared to analogous anti-CD40-antigen constructs. In normal donors, anti-CD40-CD40L-mediated delivery of Influenza M1 protein elicited M1-specific T cell expansion at lower doses compared to anti-CD40-mediated delivery. Also, on human myeloid-derived dendritic cells, anti-CD40-CD40L-melanoma gp100 peptide induced more sustained Class I antigen presentation compared to anti-CD40-gp100 peptide. In human CD40 transgenic mice, anti-CD40-CD40L-HIV-1 gp140 administered without adjuvant elicited superior antibody responses compared to anti-CD40-gp140 antigen without fused CD40L. In human CD40 mice, compared to the anti-CD40 vehicle, anti-CD40-CD40L delivery of Eα 52-68 peptide elicited proliferating of TCR I-Eα 52-68 CD4+ T cells producing cytokine IFNγ. Also, compared to controls, only anti-CD40-CD40L-Cyclin D1 vaccination of human CD40 mice reduced implanted EO771.LMB breast tumor cell growth. These data demonstrate that human CD40-CD40L antibody fused to antigens maintains highly agonistic activity and generates immune responses distinct from existing low agonist anti-CD40 targeting formats. These advantages were in vitro skewing responses towards CD8+ T cells, increased efficacy at low doses, and longevity of MHC Class I peptide display; and in mouse models, a more robust humoral response, more activated CD4+ T cells, and control of tumor growth. Thus, the anti-CD40-CD40L format offers an alternate DC-targeting platform with unique properties, including intrinsic adjuvant activity.

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