scholarly journals The race for the prize: T-cell trafficking strategies for optimal surveillance

Blood ◽  
2012 ◽  
Vol 120 (7) ◽  
pp. 1432-1438 ◽  
Author(s):  
Minyi Lee ◽  
Judith N. Mandl ◽  
Ronald N. Germain ◽  
Andrew J. Yates
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Optimization Problem ◽  
Cell Trafficking ◽  
T Cell Trafficking ◽  
Cell Responses ◽  
Major Histocompatibility Complexes ◽  
Draining Lymph Node ◽  
Slow Transit

Abstract The initiation of T-cell responses requires rare precursors to locate a draining lymph node (dLN) and encounter dendritic cells (DCs) presenting peptide-major histocompatibility complexes (pMHCs). To locate this needle in the haystack rapidly, T cells face an optimization problem—what is the most efficient trafficking strategy for surveillance and recirculation through blood? Two extremes are scanning low numbers of DCs per node with frequent recirculation, or meticulous surveillance with infrequent recirculation. Naive T cells also require stimulation by self-pMHCs. To enable efficient location of both foreign and self, has evolution settled on an optimum time for T cells to spend surveying each lymph node? Using a data-driven mathematical model, we show the most efficient strategy for detecting antigen in a dLN depends on its abundance. Detection of low-density antigen is optimized with systemically slow transit. In contrast, at high densities or if dLN egress is restricted, rapid transit through other nodes is optimal. We argue that blood-lymph recirculation dynamics facilitate a trade-off, and are consistent with dominant roles for the very early detection of rare foreign antigens in a dLN, and the efficient accumulation of signals from systemically distributed self-antigens.

An anti-CD40 activating antibody induces dendritic cell maturation and promotes autologous anti-tumor T cell responses in an in vitro mixed autologous tumor cell/lymph node cell model

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2537-2537
Author(s):  
T. B. Hunter ◽  
R. P. Gladue ◽  
S. J. Antonia
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Cell Model ◽  
T Cell Responses ◽  
Lymph Node Cell ◽  
Autologous Tumor ◽  
Cell Responses ◽  
Draining Lymph Node ◽  
Antigen Presenting

2537 Background: CD40-mediated interactions play an important role in the response to a variety of diseases, including cancer. Engagement of CD40 on antigen-presenting cells (APC) by CD40L leads to maturation and upregulation of co-stimulatory molecules, B7.1 and B7.2 (CD80 and CD86), which are requisite in the activation of T cells. Clinical trials involving immunologic interventions have shown clinical responses confirming that the immune system can be harnessed for the treatment of cancer. However, the clinical response rate has been low, signifying the need for new immunotherapeutic strategies. To this end, an agonist antibody specific for CD40 has been developed and is being evaluated as a potential anti-cancer agent. Methods: The activation capacity of anti-CD40 antibody CP-870,893 was analyzed by performing flow cytometric analysis of APC maturation markers following incubation of monocyte derived dendritic cells (DC) with the antibody. IL-12 and macrophage inflammatory protein-1α (Mip1 α) secretion were also analyzed. The effect of the antibody on anti-tumor T cell responses was tested in an autologous human model consisting of tumor cells as stimulator cells and tumor-draining lymph node cells as responders from a series of cancer patients. Results: Cultured DC treated with CP-870,893 consistently display a mature phenotype: robust upregulation of CD80, CD83, CD86 and HLA-DR expression, increased Mip1 α secretion, and the loss of antigen presenting capability. IL-12 secretion was not detected. CP-870,893 also promotes the responsiveness of lymph node derived T cells to autologous tumor, indicated by IFNγ and IL-2 ELISpot. Conclusions: These data demonstrate that CP-870,893 binds to and activates DC. A fully autologous mixed lymph node cell/tumor cell model was used to demonstrate that this activation promotes tumor-specific T cell responses. T cells from the tumor draining lymph node are not responsive to autologous tumor cells, however in the presence of CP-870,893 this unresponsiveness is reversed. These data indicate that CP-870,893 warrants further study as an immunotherapeutic agent in the treatment of cancer. No significant financial relationships to disclose.

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 Development of a novelFrancisella tularensisLive Vaccine Strain expressing ovalbumin provides insight intoFrancisella tularensis-specific CD8+T cell responses

2017 ◽  
Author(s):  
David E. Place ◽  
David R. Williamson ◽  
Yevgeniy Yuzefpolskiy ◽  
Bhuvana Katkere ◽  
Surojit Sarkar ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Vaccine Strain ◽  
T Cell Responses ◽  
T Cell Response ◽  
Effective Vaccine ◽  
Cell Responses ◽  
Virulent Strains ◽  
Draining Lymph Node

ABSTRACTProgress towards a safe and effective vaccine for the prevention of tularemia has been hindered by a lack of knowledge regarding the correlates of protective adaptive immunity and a lack of tools to generate this knowledge. CD8+T cells are essential for protective immunity against virulent strains ofFrancisella tularensis, but to-date, it has not been possible to study these cells in a pathogen-specific manner. Here, we report the development of a tool for expression of the model antigen ovalbumin (OVA) inF. tularensis, which allows for the study of CD8+T cell responses to the bacterium. We demonstrate that in response to intranasal infection with theF. tularensisLive Vaccine Strain, pathogen-specific CD8+T cells expand after the first week and produce IFN-γ but not IL-17. Effector and central memory subsets develop with disparate kinetics in the lungs, draining lymph node and spleen. Notably,F. tularensis-specific cells are poorly retained in the lungs after clearance of infection. We also show that intranasal vaccination leads to more pathogen-specific CD8+T cells in the lung-draining lymph node compared to scarification vaccination, but that an intranasal booster overcomes this difference. Together, our data show that this novel tool can be used to study multiple aspects of the CD8+T cell response toF. tularensis. Use of this tool will enhance our understanding of immunity to this deadly pathogen.

scholarly journals CCR2- and Flt3-Dependent Inflammatory Conventional Type 2 Dendritic Cells Are Necessary for the Induction of Adaptive Immunity by the Human Vaccine Adjuvant System AS01

2021 ◽  
Vol 11 ◽  
Author(s):  
Cedric Bosteels ◽  
Kaat Fierens ◽  
Sofie De Prijck ◽  
Justine Van Moorleghem ◽  
Manon Vanheerswynghels ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Lymph Node ◽  
T Cell ◽  
Adaptive Immunity ◽  
T Cell Responses ◽  
Cell Responses ◽  
Adaptive Immune ◽  
Adjuvant System ◽  
Draining Lymph Node

The Adjuvant System AS01 contains monophosphoryl lipid A (MPL) and the saponin QS-21 in a liposomal formulation. AS01 is included in recently developed vaccines against malaria and varicella zoster virus. Like for many other adjuvants, induction of adaptive immunity by AS01 is highly dependent on the ability to recruit and activate dendritic cells (DCs) that migrate to the draining lymph node for T and B cell stimulation. The objective of this study was to more precisely address the contribution of the different conventional (cDC) and monocyte-derived DC (MC) subsets in the orchestration of the adaptive immune response after immunization with AS01 adjuvanted vaccine. The combination of MPL and QS-21 in AS01 induced strong recruitment of CD26+XCR1+ cDC1s, CD26+CD172+ cDC2s and a recently defined CCR2-dependent CD64-expressing inflammatory cDC2 (inf-cDC2) subset to the draining lymph node compared to antigen alone, while CD26-CD64+CD88+ MCs were barely detectable. At 24 h post-vaccination, cDC2s and inf-cDC2s were superior amongst the different subsets in priming antigen-specific CD4+ T cells, while simultaneously presenting antigen to CD8+ T cells. Diphtheria toxin (DT) mediated depletion of all DCs prior to vaccination completely abolished adaptive immune responses, while depletion 24 h after vaccination mainly affected CD8+ T cell responses. Vaccinated mice lacking Flt3 or the chemokine receptor CCR2 showed a marked deficit in inf-cDC2 recruitment and failed to raise proper antibody and T cell responses. Thus, the adjuvant activity of AS01 is associated with the potent activation of subsets of cDC2s, including the newly described inf-cDC2s.

The Rac activator Tiam1 controls efficient T-cell trafficking and route of transendothelial migration

Blood ◽  
2009 ◽  
Vol 113 (24) ◽  
pp. 6138-6147 ◽  
Author(s):  
Audrey Gérard ◽  
Rob A. van der Kammen ◽  
Hans Janssen ◽  
Saskia I. Ellenbroek ◽  
John G. Collard
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
T Cell ◽  
Transendothelial Migration ◽  
Contact Hypersensitivity ◽  
Cell Trafficking ◽  
T Cell Trafficking ◽  
Cell Arrest

Abstract Migration toward chemoattractants is a hallmark of T-cell trafficking and is essential to produce an efficient immune response. Here, we have analyzed the function of the Rac activator Tiam1 in the control of T-cell trafficking and transendothelial migration. We found that Tiam1 is required for chemokine- and S1P-induced Rac activation and subsequent cell migration. As a result, Tiam1-deficient T cells show reduced chemotaxis in vitro, and impaired homing, egress, and contact hypersensitivity in vivo. Analysis of the T-cell transendothelial migration cascade revealed that PKCζ/Tiam1/Rac signaling is dispensable for T-cell arrest but is essential for the stabilization of polarization and efficient crawling of T cells on endothelial cells. T cells that lack Tiam1 predominantly transmigrate through individual endothelial cells (transcellular migration) rather than at endothelial junctions (paracellular migration), suggesting that T cells are able to change their route of transendothelial migration according to their polarization status and crawling capacity.

scholarly journals Antigen-Specific TGF-β–Induced Regulatory T Cells Secrete Chemokines, Regulate T Cell Trafficking, and Suppress Ongoing Autoimmunity

2011 ◽  
Vol 187 (4) ◽  
pp. 1745-1753 ◽  
Author(s):  
Thanh-Long M. Nguyen ◽  
Nicole L. Sullivan ◽  
Mark Ebel ◽  
Ryan M. Teague ◽  
Richard J. DiPaolo
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Trafficking ◽  
T Cell Trafficking

Combined Treatment with Short Synthetic Anti-Lymphoma Peptide and CpG ODN; A Therapeutic Vaccine Which cures the A20 Lymphoma in Balb/C Mice.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1586-1586
Author(s):  
Arne Kolstad ◽  
Roch Houot ◽  
Gerd Berge ◽  
Øystein Rekdal ◽  
Debra Czerwinski ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Combined Treatment ◽  
Therapeutic Vaccine ◽  
Immunological Memory ◽  
Separate Experiment ◽  
Lymphoma Cells ◽  
Draining Lymph Node ◽  
Ifn Γ

Abstract Background. The short synthetic peptide 302 has been shown to induce rapid membrane disruption of lymphoma cells in vitro and necrosis of local tumors in the A20 lymphoma model in Balb/c mice. In order to stimulate the immune system to generate an anti-tumor response we designed a model where intra-tumor injections of peptide 302 was combined with sc injections of the Toll-like receptor 9 binding synthetic oligonucleotide CpG 1826. Methods. Balb/c mice were inoculated with A20 lymphoma cells sub-cutaneously (s.c.) on the abdomen. When the tumors reached a size of 5–7 mm, 302 peptide was administered directly into the tumors on days 1 and 6. CpG 1826 was injected s.c. on days 1–4 and 6–8. Tumor growth was measured repeatedly during follow-up. A20-specific T-cell responses were detected by culturing peripheral blood lymphocytes from treated animals for 24 hours with A20 lymphoma cells and analyzing for intracellular IFN-γ production by flow cytometry. To dissect the role of T-cell subtypes, the treatment was performed in animals depleted for CD4 or CD8 positive T-cells. In order to show A20 specific immunological memory, cured animals were re-challenged with the A20 lymphoma or the carcinoma cell line CT26. Results. Combined treatment with peptide 302 and CpG 1826 cured 8 out of 10 mice, compared to only 2 out of 10 mice who received peptide 302 alone or CpG 1826 alone. Cured mice were followed for 9 weeks without relapsing. Similar results with the combination of peptide 302 and CpG were observed in a separate experiment. The highest cure rate was achieved when injecting CpG 1826 s.c. in the tumors draining lymph node area as compared to administration of CPG 1826 in a non-draining lymph node region or intra-peritoneal. Animals treated with peptide 302 + CpG 1826 or CpG 1826 alone developed CD8-specific IFN-γ responses against A20 cells. In one separate experiment CD8 knock-out mice did not respond to the treatment, unlike animals depleted for CD4+ cells and normal mice. Only 1 out of 10 cured animals re-challenged with the A20 lymphoma developed a new tumor, a result that was reproduced in a second experiment. Conclusion: Treatment with intra-tumor injections of the anti-lymphoma peptide 302 in combination with CpG 1826 s.c. in the draining lymph node region cured established A20 tumors, induced tumor-specific CD8 positive tumor-reactive T-cells, and induced specific immunological memory. This principle represents a novel therapeutic vaccine approach.

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