scholarly journals Lymph node swelling combined with temporary effector T cell retention aids T cell response in a model of adaptive immunity

2021 ◽  
Vol 18 (185) ◽  
Author(s):  
Sarah C. Johnson ◽  
Jennifer Frattolin ◽  
Lowell T. Edgar ◽  
Mohammad Jafarnejad ◽  
James E. Moore Jr
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Adaptive Immune Response ◽  
T Cell Response ◽  
Negative Effects ◽  
Macro Scale ◽  
Lymph Node Swelling ◽  
Sphingosine 1 Phosphate ◽  
Retention Aids ◽  
The Impact

Swelling of lymph nodes (LNs) is commonly observed during the adaptive immune response, yet the impact on T cell (TC) trafficking and subsequent immune response is not well known. To better understand the effect of macro-scale alterations, we developed an agent-based model of the LN paracortex, describing the TC proliferative response to antigen-presenting dendritic cells alongside inflammation-driven and swelling-induced changes in TC recruitment and egress, while also incorporating regulation of the expression of egress-modulating TC receptor sphingosine-1-phosphate receptor-1. Analysis of the effector TC response under varying swelling conditions showed that swelling consistently aided TC activation. However, subsequent effector CD8 + TC production was reduced in scenarios where swelling occurred too early in the TC proliferative phase or when TC cognate frequency was low due to increased opportunity for TC exit. Temporarily extending retention of newly differentiated effector TCs, mediated by sphingosine-1-phosphate receptor-1 expression, mitigated any negative effects of swelling by allowing facilitation of activation to outweigh increased access to exit areas. These results suggest that targeting temporary effector TC retention and egress associated with swelling offers new ways to modulate effector TC responses in, for example, immuno-suppressed patients and to optimize of vaccine design.

scholarly journals Regulation of peripheral T cell activation by calreticulin

2006 ◽  
Vol 203 (2) ◽  
pp. 461-471 ◽  
Author(s):  
Simona Porcellini ◽  
Elisabetta Traggiai ◽  
Ursula Schenk ◽  
Denise Ferrera ◽  
Michela Matteoli ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Adaptive Immune Response ◽  
T Cell Response ◽  
Mitogen Activated Protein Kinase ◽  
Immunodeficient Mice ◽  
Adaptive Immune ◽  
The Impact

Regulated expression of positive and negative regulatory factors controls the extent and duration of T cell adaptive immune response preserving the organism's integrity. Calreticulin (CRT) is a major Ca2+ buffering chaperone in the lumen of the endoplasmic reticulum. Here we investigated the impact of CRT deficiency on T cell function in immunodeficient mice reconstituted with fetal liver crt−/− hemopoietic progenitors. These chimeric mice displayed severe immunopathological traits, which correlated with a lower threshold of T cell receptor (TCR) activation and exaggerated peripheral T cell response to antigen with enhanced secretion of inflammatory cytokines. In crt−/− T cells TCR stimulation induced pulsatile cytosolic elevations of Ca2+ concentration and protracted accumulation of nuclear factor of activated T cells in the nucleus as well as sustained activation of the mitogen-activated protein kinase pathways. These observations support the hypothesis that CRT-dependent shaping of Ca2+ signaling critically contributes to the modulation of the T cell adaptive immune response.

scholarly journals P02.03 Microwave ablation enhances tumor-specific immune response in patients with hepatocellular carcinoma

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A21.1-A21
Author(s):  
E Staib ◽  
K Leuchte ◽  
M Thelen ◽  
P Gödel ◽  
A Lechner ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Thermal Ablation ◽  
Microwave Ablation ◽  
T Cell Response ◽  
Tumor Control ◽  
Free Survival ◽  
Interleukin 5 ◽  
The Impact

BackgroundThermal ablative therapies, such as microwave ablation (MWA) or radiofrequency ablation (RFA), are standard treatments for HCC. In addition to the local tumor destruction, abscopal effects (a reduction of a tumor mass in areas that were not included in the thermal ablation) could be observed. These systemic effects may be mediated by anti-tumor immune response, which has been described for RFA. MWA is rapidly replacing RFA, but systemic immunostimulatory effects of MWA treatment have been poorly studied.Materials and MethodsPatients receiving MWA for localized HCC were included in this study. Effects of MWA on peripheral blood mononuclear cells (PBMC) of HCC patients treated with MWA were analyzed by multicolor flow cytometry. Tumor-specific immune responses against 7 shared tumor antigens were analyzed using peptide pools in 3-color Fluorospot assays (Interferon-y/Interleukin-5/Interleukin-10). The impact of type, density and localization of tumor-infiltrating lymphocytes was assessed by immunohistochemistry (IHC) of CD3, CD4, CD8, FoxP3, CD38 and CD20 and digital image analyses (Immunoscore) of tumor specimens in an additional cohort of patients who received combined surgical resection and thermal ablation.ResultsWhile comprehensive flow cytometric analyses in sequential samples (day 0, 7 and 90) of a prospective patient cohort (n=23) demonstrated only moderate effects of MWA on circulating immune cell subsets, Fluorospot analyses revealed de novo or enhanced tumor-specific immune responses in 30% of these patients. This anti-tumor immune response was related to tumor control. Interferon-y and Interleukin-5 T cell responses against cancer testis antigens were more frequent in patients with a long-time remission (>12 months) after MWA (7/16) compared to patients suffering from an early relapse (0/13 patients). Presence of tumor-specific T cell response (Interferon-y and/or Interleukin-5) was associated to longer progression-free survival (15.0 vs. 10.0 months). Immunohistochemical analyses of resected tumor samples revealed that a high T cell infiltration in a second tumor lesion at the time of thermal ablation was associated with superior disease-free survival (37.4 vs. 13.1 months).ConclusionsOur data demonstrates remarkable immune-related effects of MWA in HCC patients. This study and provides additional evidence for a combination of thermal ablation and immunotherapy in this challenging disease.Funding‘Koeln Fortune’ and ‘CAP-CMMC’ local research grant (to P.G. and H.A.S.) supported our research.Disclosure InformationE. Staib: None. K. Leuchte: None. M. Thelen: None. P. Gödel: None. A. Lechner: None. P. Zentis: None. M. Garcia-Marquez: None. D. Waldschmidt: None. R.R. Datta: None. R. Wahba: None. C. Wybranski: None. T. Zander: None. A. Quaas: None. U. Drebber: None. D.L. Stippel: None. C. Bruns: None. K. Wennhold: None. M. von Bergwelt-Baildon: None. H.A. Schlösser: None.

scholarly journals Preferential CD8 rather than CD4 T-cell response to wear particles of polyether-ether-ketone and highly cross-linked polyethylene

RSC Advances ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 1866-1874 ◽  
Author(s):  
Zhe Du ◽  
Shujun Wang ◽  
You Wang
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cell Response ◽  
Adaptive Immune Response ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Wear Particles ◽  
Adaptive Immune ◽  
Polyether Ether Ketone ◽  
Ether Ketone

Enriching the understanding of the effects of the particles on the adaptive immune response.

scholarly journals Immune Response Induced by Three Mycobacterium bovis BCG Substrains with Diverse Regions of Deletion in a C57BL/6 Mouse Model

2008 ◽  
Vol 15 (5) ◽  
pp. 750-756 ◽  
Author(s):  
S. M. Irwin ◽  
A. Goodyear ◽  
A. Keyser ◽  
R. Christensen ◽  
J. M. Troudt ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Mouse Model ◽  
Immune Responses ◽  
Mycobacterium Bovis ◽  
Adaptive Immune Response ◽  
T Cell Response ◽  
Interleukin 12 ◽  
Bacterial Burden ◽  
Equal Capacity

ABSTRACT This study was performed to examine the adaptive immune response generated by three Mycobacterium bovis bacillus Calmette-Guérin (BCG) substrains to determine if the number of genomic regions of deletion played a significant role in determining the magnitude of the immune response or affected their ability to reduce the bacterial burden following low-dose aerosol challenge with a virulent M. tuberculosis strain. BCG Connaught, Pasteur, and Sweden were chosen as representative substrains, as they possessed many, intermediate, and few regions of deletion, respectively, as a result of changes in the genome in various regions. Mice were vaccinated subcutaneously and were then examined at 14, 21, and 42 days postvaccination. BCG was observed in the spleen, lung, and lymph nodes. BCG Connaught induced a greater pulmonary T-cell response than the other two substrains at day 14 postvaccination, although by 42 days postvaccination activated T-cell levels dropped to the levels observed in control mice for all three substrains. Among the three substrains, BCG Connaught induced significantly greater levels of interleukin-12 in bone marrow-derived macrophage cultures. Mice challenged at days 14, 21, and 42 postvaccination displayed an equal capacity to reduce the bacterial burden in the lungs and spleen. The data provide evidence that although the BCG substrains generated qualitatively and quantitatively different immune responses, they induced similar reductions in the bacterial burden against challenge with a virulent M. tuberculosis strain in the mouse model of tuberculosis. The data raise questions about the assessment of vaccine immune responses and the relationship to a vaccine's ability to reduce the bacterial burden.

scholarly journals Modelling the effects of lymph node swelling on T-cell response

2020 ◽  
Author(s):  
Sarah C Johnson ◽  
Jennifer Frattolin ◽  
Lowell T. Edgar ◽  
Mohammad Jafarnejad ◽  
James E. Moore
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Cell Trafficking ◽  
T Cell Trafficking ◽  
Effector T Cell ◽  
Sphingosine 1 Phosphate

AbstractSwelling of the lymph nodes is commonly observed during the adaptive immune response, yet its impacts on T cell trafficking and subsequent immune response are not well known. To better understand the effect of macro-scale alterations in the lymph node, we developed an agent-based model of the lymph node paracortex, describing T cell trafficking and response to antigen-presenting dendritic cells alongside swelling-induced changes in T cell recruitment and egress, and regulation of expression of egress-modulating T cell receptor Sphingosine-1-phosphate receptor-1. Validation of the model was achieved with in-silico replication of a range of published in-vivo and cell culture experiments. Analysis of CD4+ and CD8+ effector T cell response under varying swelling conditions showed that paracortical swelling aided initial T cell activation but could inhibit subsequent effector CD8+ T cell production if swelling occurs too early in the T cell proliferative phase. A global sensitivity analysis revealed that the effects of some parameters switch from aiding to inhibiting T cell response over a ten day response period. Furthermore, temporarily extending retention of newly differentiated effector T cells, mediated by Sphingosine-1-phosphate receptor-1 expression, mitigated some of the effects of early paracortical swelling. These results suggest that targeting the timing of lymph node swelling and temporary effector T cell retention may offer new ways to manipulate immune response.Author summaryWithin the lymph nodes the interaction of T cells and antigen presenting cells play a crucial role in initiating the adaptive immune response, resulting in effector T cells that travel to the infection site. Accompanying swelling of lymph nodes is commonly observed, yet the impact on T cell trafficking through the node and the subsequent immune response are not well known. We developed a novel agent-based model of a lymph node, describing immune response-induced expansion, contraction and changes in T cell recruitment and egress. We also describe the regulation of T cell expression of the Sphingosine-1-phosphate receptor-1, which is known to play an important role in T cell trafficking. We found that although swelling aids T cell activation, too early an increase in paracortical volume hinders the CD8+ effector T cell response. We also found that temporarily maintaining the down-regulation of Sphingosine-1-phosphate receptor-1 expression on newly differentiated effector T cells greatly increased the overall effector T cell output, and could counteract the loss in effector TC production due to early swelling. Our findings suggest that targeting the timing of lymph node swelling and temporary effector T cell retention may offer new ways to manipulate immune response.

scholarly journals Failure of BCG Necessitates to the Development of New Novel Vaccine

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Meena S ◽  
◽  
Goutam P ◽  
Meena LS ◽  
◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Vaccine Development ◽  
Adaptive Immune Response ◽  
Outer Part ◽  
T Cell Response ◽  
Mycobacterial Antigen ◽  
Mycobacterium Tuberculosis H37rv ◽  
Sustained Effects ◽  
The One

The only vaccine available for the deadly disease tuberculosis is Bacillus- Calmette-Guerin (BCG), which is an attenuated vaccine of Mycobacterium bovis. Although this vaccine boosts immune response but it is effective only for 10-20 years, after this there is need to develop immunity against Mycobacterium tuberculosis H37Rv (M. tuberculosis). As the vaccine is botched to provide sustained effects and to protect against disseminated forms of Tuberculosis (TB), it needs a component to heighten antigen specific immune reactions when used in combination with particular vaccine antigens that can also modulate the immune responses to an antigen to advance them. Adjuvants are the one such factor that can be used in vaccines to crack such problems. Many vaccines are under clinical trials in which subunit vaccine has taken attention because they are safer and can be standardized. There are many adjuvants which have been tested in combinations with BCG to increase the activity of vaccine. Mycobacterial antigen 85 A, B, C, present at outer part of cell wall and have great potential as therapeutic approach towards tuberculosis. MPT64 increases T-cell response in tuberculosis patients but there are less evidence about the role of this secreted mycobacterial protein in patients. ESAT 6 is effective T cell antigen and also pore forming toxin which is crucial for the virulence of bacterium. ESAT 6 separately or in compound form with its chaperone CFP- 10 form, regulates host immune response. They efficiently modify innate and adaptive immune response. This review provides an insight in the direction of the vaccine development on the basis of pre-existing credentials.

scholarly journals SARS-CoV-2 Human T cell Epitopes: adaptive immune response against COVID-19.

2021 ◽  
Author(s):  
Alba Grifoni ◽  
John Sidney ◽  
Randi Vita ◽  
Bjoern Peters ◽  
Shane Crotty ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Adaptive Immune Response ◽  
T Cell Epitopes ◽  
Adaptive Immune ◽  
Human T Cell

scholarly journals IMGT® Biocuration and Comparative Analysis of Bos taurus and Ovis aries TRA/TRD Loci

Genes ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 30
Author(s):  
Perrine Pégorier ◽  
Morgane Bertignac ◽  
Viviane Nguefack Ngoune ◽  
Géraldine Folch ◽  
Joumana Jabado-Michaloud ◽  
...  
Keyword(s):  
Immune Response ◽  
Comparative Analysis ◽  
T Cell ◽  
T Cell Receptors ◽  
Bos Taurus ◽  
Homo Sapiens ◽  
Adaptive Immune Response ◽  
Ovis Aries ◽  
Cell Receptors ◽  
Adaptive Immune

The adaptive immune response provides the vertebrate immune system with the ability to recognize and remember specific pathogens to generate immunity, and mount stronger attacks each time the pathogen is encountered. T cell receptors are the antigen receptors of the adaptive immune response expressed by T cells, which specifically recognize processed antigens, presented as peptides by the highly polymorphic major histocompatibility (MH) proteins. T cell receptors (TR) are divided into two groups, αβ and γδ, which express distinct TR containing either α and β, or γ and δ chains, respectively. The TRα locus (TRA) and TRδ locus (TRD) of bovine (Bos taurus) and the sheep (Ovis aries) have recently been described and annotated by IMGT® biocurators. The aim of the present study is to present the results of the biocuration and to compare the genes of the TRA/TRD loci among these ruminant species based on the Homo sapiens repertoire. The comparative analysis shows similarities but also differences, including the fact that these two species have a TRA/TRD locus about three times larger than that of humans and therefore have many more genes which may demonstrate duplications and/or deletions during evolution.

scholarly journals Checkpoint blockade accelerates a novel switch from an NKT-driven TNFα response toward a T cell driven IFN-γ response within the tumor microenvironment

2021 ◽  
Vol 9 (6) ◽  
pp. e002269
Author(s):  
Shota Aoyama ◽  
Ryosuke Nakagawa ◽  
Satoshi Nemoto ◽  
Patricio Perez-Villarroel ◽  
James J Mulé ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Ex Vivo ◽  
T Cell Response ◽  
Effector Function ◽  
Checkpoint Blockade ◽  
Necrosis Factor Alpha ◽  
Ifn Γ

BackgroundThe temporal response to checkpoint blockade (CB) is incompletely understood. Here, we profiled the tumor infiltrating lymphocyte (TIL) landscape in response to combination checkpoint blockade at two distinct timepoints of solid tumor growth.MethodsC57BL/6 mice bearing subcutaneous MC38 tumors were treated with anti-PD-1 and/or anti-CTLA-4 antibodies. At 11 or 21 days, TIL phenotype and effector function were analyzed in excised tumor digests using high parameter flow cytometry. The contributions of major TIL populations toward overall response were then assessed using ex vivo cytotoxicity and in vivo tumor growth assays.ResultsThe distribution and effector function among 37 distinct TIL populations shifted dramatically between early and late MC38 growth. At 11 days, the immune response was dominated by Tumor necrosis factor alpha (TNFα)-producing NKT, representing over half of all TIL. These were accompanied by modest frequencies of natural killer (NK), CD4+, or CD8+ T cells, producing low levels of IFN-γ. At 21 days, NKT populations were reduced to a combined 20% of TIL, giving way to increased NK, CD4+, and CD8+ T cells, with increased IFN-γ production. Treatment with CB accelerated this switch. At day 11, CB reduced NKT to less than 20% of all TIL, downregulated TNFα across NKT and CD4+ T cell populations, increased CD4+ and CD8+ TIL frequencies, and significantly upregulated IFN-γ production. Degranulation was largely associated with NK and NKT TIL. Blockade of H-2kb and/or CD1d during ex vivo cytotoxicity assays revealed NKT has limited direct cytotoxicity against parent MC38. However, forced CD1d overexpression in MC38 cells significantly diminished tumor growth, suggesting NKT TIL exerts indirect control over MC38 growth.ConclusionsDespite an indirect benefit of early NKT activity, CB accelerates a switch from TNFα, NKT-driven immune response toward an IFN-γ driven CD4+/CD8+ T cell response in MC38 tumors. These results uncover a novel NKT/T cell switch that may be a key feature of CB response in CD1d+ tumors.

scholarly journals Nano-Microparticle Platforms in Developing Next-Generation Vaccines

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 606
Author(s):  
Giuseppe Cappellano ◽  
Hugo Abreu ◽  
Chiara Casale ◽  
Umberto Dianzani ◽  
Annalisa Chiocchetti
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cell Response ◽  
Humoral Response ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Next Generation ◽  
Emerging Viruses ◽  
Whole Cells ◽  
Effector Functions

The first vaccines ever made were based on live-attenuated or inactivated pathogens, either whole cells or fragments. Although these vaccines required the co-administration of antigens with adjuvants to induce a strong humoral response, they could only elicit a poor CD8+ T-cell response. In contrast, next-generation nano/microparticle-based vaccines offer several advantages over traditional ones because they can induce a more potent CD8+ T-cell response and, at the same time, are ideal carriers for proteins, adjuvants, and nucleic acids. The fact that these nanocarriers can be loaded with molecules able to modulate the immune response by inducing different effector functions and regulatory activities makes them ideal tools for inverse vaccination, whose goal is to shut down the immune response in autoimmune diseases. Poly (lactic-co-glycolic acid) (PLGA) and liposomes are biocompatible materials approved by the Food and Drug Administration (FDA) for clinical use and are, therefore, suitable for nanoparticle-based vaccines. Recently, another candidate platform for innovative vaccines based on extracellular vesicles (EVs) has been shown to efficiently co-deliver antigens and adjuvants. This review will discuss the potential use of PLGA-NPs, liposomes, and EVs as carriers of peptides, adjuvants, mRNA, and DNA for the development of next-generation vaccines against endemic and emerging viruses in light of the recent COVID-19 pandemic.

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