Design of PD-1-decorated nanocages targeting tumor-draining lymph node for promoting T cell activation

Two subsets of murine splenic dendritic cells, derived from distinct precursors, can be distinguished by surface expression of CD8α homodimers. The functions of the two subsets remain controversial, although it has been suggested that the lymphoid-derived (CD8α+) subset induces tolerance, whereas the myeloid-derived (CD8α−) subset has been shown to prime naive T cells and to generate memory responses. To study their capacity to prime or tolerize naive CD4+ T cells in vivo, purified CD8α+ or CD8α− dendritic cells were injected subcutaneously into normal mice. In contrast to CD8α− dendritic cells, the CD8α+ fraction failed to traffic to the draining lymph node and did not generate responses to intravenous peptide. However, after in vitro pulsing with peptide, strong in vivo T cell responses to purified CD8α+ dendritic cells could be detected. Such responses may have been initiated via transfer of peptide–major histocompatibility complex complexes to migratory host CD8α− dendritic cells after injection. These data suggest that correlation of T helper cell type 1 (Th1) and Th2 priming with injection of CD8α+ and CD8α− dendritic cells, respectively, may not result from direct T cell activation by lymphoid versus myeloid dendritic cells, but rather from indirect modification of the response to immunogenic CD8α− dendritic cells by CD8α+ dendritic cells.

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Intramuscular vaccination targeting mucosal tumor draining lymph node enhances integrins-mediated CD8+ T cell infiltration to control mucosal tumor growth

OncoImmunology ◽

10.1080/2162402x.2018.1463946 ◽

2018 ◽

pp. e1463946 ◽

Cited By ~ 1

Author(s):

Jin Qiu ◽

Shiwen Peng ◽

Andrew Yang ◽

Ying Ma ◽

Liping Han ◽

...

Keyword(s):

Lymph Node ◽

T Cell ◽

Tumor Growth ◽

Cd8 T Cell ◽

Cell Infiltration ◽

T Cell Infiltration ◽

Draining Lymph Node ◽

Tumor Draining Lymph Node

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A virtual lymph node model to dissect the requirements for T‐cell activation by synapses and kinapses

Immunology and Cell Biology ◽

10.1038/icb.2016.36 ◽

2016 ◽

Vol 94 (7) ◽

pp. 680-688 ◽

Cited By ~ 7

Author(s):

Hélène D Moreau ◽

Gib Bogle ◽

Philippe Bousso

Keyword(s):

Lymph Node ◽

T Cell ◽

T Cell Activation ◽

Cell Activation

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Targeting Notch Signaling as a Safe and Effective Treatment for Autoimmune and Lymphoproliferative Diseases.

Blood ◽

10.1182/blood.v108.11.647.647 ◽

2006 ◽

Vol 108 (11) ◽

pp. 647-647

Author(s):

David T. Teachey ◽

Alix Seif ◽

Junior Hall ◽

Theresa Ryan ◽

Gregor Reid ◽

...

Keyword(s):

Lymph Node ◽

T Cell ◽

Lymph Nodes ◽

Notch Signaling ◽

Antibody Titer ◽

T Cell Activation ◽

Peripheral Blood ◽

Cell Activation ◽

Notch Signaling Pathway ◽

Lymphoproliferative Diseases

Abstract Patients and mice with both the autoimmune lymphoproliferative syndrome (ALPS) and systemic lupus erythematosis (SLE) have T cell dysregulation and produce both abnormal, activated T lymphocytes and an unusual T cell population, Double Negative T cells (DNTs, cell phenotype: CD3+, CD4-, CD8-, TCR αβ+). The Notch signaling pathway is important in T cell lineage development, including development of DNTs, and in T cell activation. Inhibitors of this pathway are in clinical development, because inhibiting Notch signaling may be effective in treating Alzheimer’s disease and T cell leukemia. We hypothesized that inhibiting Notch signaling would be effective in reducing symptoms and treating the disease in patients with ALPS and SLE by both reducing the production of abnormal DNTs and by blocking aberrant T cell activation. We tested this hypothesis using two murine models of defective lymphocyte apoptosis, CBA-lprcg and MRL-lpr. CBA-lprcg has a phenotype similar to human ALPS, as these mice develop massive lymphadenopathy and splenomegaly with DNT infiltration of these organs. In the MRL-lpr background, the apoptotic defect manifests itself in a phenotype similar to human SLE, as these mice develop autoantibodies, glomerulonephritis, and a vasculitic dermatitis. Mice were randomized to treatment with a low dose (5mg/kg/day) of the α-secretase inhibitor, DAPT, for 5 days a week by gavage versus vehicle. Treatment response was followed with assessment of DNTs in peripheral blood and lymphoid tissue by flow cytometry, by monitoring of lymph node and spleen size with small animal ultrasound, and ELISA to quantify antibody titer for anti-dsDNA IgG specific antibodies. We found a profound and statistically significant decrease in antibody titer (p = 0.02), lymphadenopathy (p = 0.006), and splenomegaly (p = 0.008) after only 4 weeks, comparing mice treated with DAPT to control animals (Table). Treated mice also had decreased absolute DNTs in their spleens (p = 0.02) and lymph nodes (p = 0.04) compared to control. Treated mice had a trend toward decreased absolute DNTs in peripheral blood; however, more animals are being enrolled on this study to reach 80% power to detect a statistically significant difference. Finally, treated MRL-lpr mice showed stabilization or improvement in their characteristic vasculitic skin disease, whereas control animals showed progression. We found the response to DAPT was durable, having treated mice for over 12 weeks. Also, with this dosing schema, mice experienced no toxicity. They did not manifest any gastrointestinal symptoms, as have been reported with other γ-secretase inhibitors. In summary, inhibiting the Notch signaling pathway appears to be a safe and well-tolerated means of treating autoimmune and lymphoproliferative diseases. This is the first report to use γ-secretase inhibitors to treat non-malignant, T-lymphocyte mediated disease. Disease Parameter(1) DAPT Treated(2) Vehicle Control(2) p value (1) Averge antibody titer, volume of lymph nodes, and area of spleens were similar and not statistically different between groups at initiation of treatment; (2) average (range) after 4 weeks of treatment Lymph node volume by ultrasound (mm3) 360 (170–550) 780 (366–1043) p = 0.006 Splenic area by ultrasound (mm2) 48 (27–73) 159 (69–336) p = 0.008 anti-dsDNA IgG antibody titer (ug/ml) 450 (340–560) 1350 (1260–1410) p = 0.02

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Functional Divergence among CD103+ Dendritic Cell Subpopulations following Pulmonary Poxvirus Infection

Journal of Virology ◽

10.1128/jvi.00892-10 ◽

2010 ◽

Vol 84 (19) ◽

pp. 10191-10199 ◽

Cited By ~ 31

Author(s):

Nicole M. Beauchamp ◽

Rhea Y. Busick ◽

Martha A. Alexander-Miller

Keyword(s):

Lymph Node ◽

T Cell ◽

Dendritic Cell ◽

T Cell Activation ◽

Cell Activation ◽

Functional Divergence ◽

T Cell Response ◽

Functional Capabilities ◽

Cell Subpopulations ◽

Antigen Presenting

ABSTRACT A large number of dendritic cell (DC) subsets have now been identified based on the expression of a distinct array of surface markers as well as differences in functional capabilities. More recently, the concept of unique subsets has been extended to the lung, although the functional capabilities of these subsets are only beginning to be explored. Of particular interest are respiratory DCs that express CD103. These cells line the airway and act as sentinels for pathogens that enter the lung, migrating to the draining lymph node, where they add to the already complex array of DC subsets present at this site. Here we assessed the contributions of these individual populations to the generation of a CD8+ T-cell response following respiratory infection with poxvirus. We found that CD103+ DCs were the most effective antigen-presenting cells (APC) for naive CD8+ T-cell activation. Surprisingly, we found no evidence that lymph node-resident or parenchymal DCs could prime virus-specific cells. The increased efficacy of CD103+ DCs was associated with the increased presence of viral antigen as well as high levels of maturation markers. Within the CD103+ DCs, we observed a population that expressed CD8α. Interestingly, cells bearing CD8α were less competent for T-cell activation than their CD8α− counterparts. These data show that lung-migrating CD103+ DCs are the major contributors to CD8+ T-cell activation following poxvirus infection. However, the functional capabilities of cells within this population differ with the expression of CD8, suggesting that CD103+ cells may be divided further into distinct subsets.

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Prior Exposure to Ortho-Phthalaldehyde Augments IgE-Mediated Immune Responses to Didecyldimethylammonium Chloride: Potential for 2 Commonly Used Antimicrobials to Synergistically Enhance Allergic Disease

Toxicological Sciences ◽

10.1093/toxsci/kfaa112 ◽

2020 ◽

Vol 178 (1) ◽

pp. 127-137

Author(s):

Hillary L Shane ◽

Ewa Lukomska ◽

Lisa Weatherly ◽

Rachel Baur ◽

Stacey E Anderson

Keyword(s):

Lymph Node ◽

T Cell ◽

B Cells ◽

Immune Responses ◽

Allergic Disease ◽

Cell Activation ◽

Immunological Mechanisms ◽

Draining Lymph Node ◽

Ige Mediated

Abstract Health-care workers have an increased incidence of allergic disease compared with the general public and are exposed to a variety of high-level disinfectants. Although exposure to these agents has been associated with allergic disease, findings between epidemiology and animal studies often conflict respecting immunological mechanisms. Therefore, we hypothesized that previous exposure to a representative IgE-mediated sensitizer (ortho-phthalaldehyde [OPA]) alters immune responses to a representative T-cell-mediated sensitizer (didecyldimethlyammonium chloride [DDAC]). Here, BALB/c mice were topically exposed to OPA (0.5%) for 3 days, rested, then topically exposed to DDAC (0.0625%, 0.125%, and 0.25%) for 14 days. Coexposure resulted in phenotypic changes in draining lymph node (dLN) cells, including a decreased frequency of CD8+ T cells and increased frequency and number of B cells compared with DDAC-only treated mice. The coexposed mice also had enhanced Th2 responses, including significant alterations in: dLN Il4 (increased), B-cell activation (increased), CD8+ T-cell activation (decreased), and local and systemic IgE production (increased). These changes were not observed if mice were exposed to DDAC prior to OPA. Exposure to OPA alone shows Th2 skewing, indicated by increased activation of skin type 2 innate lymphoid cells, increased frequency and activation of draining lymph node B cells, and increased levels of type 2 cytokines. These findings suggest that the OPA-induced immune environment may alter the response to DDAC, resulting in increased IgE-mediated immune responses. This data may partially explain the discordance between epidemiological and laboratory studies regarding disinfectants and provide insight into the potential immunological implications of mixed chemical exposures.

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Hepatic AAV Gene Transfer of Cytoplasmic Transgene Induces Transgene Product-Specific T Cell Activation Initially in the Liver and Celiac Lymph Node Preceding Treg Induction

Blood ◽

10.1182/blood.v126.23.3241.3241 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3241-3241

Author(s):

Roland W. Herzog ◽

George Q. Perrin

Keyword(s):

T Cells ◽

Lymph Node ◽

T Cell ◽

Gene Transfer ◽

Antigen Presentation ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Lymphoid Organs ◽

Activated T Cells

Abstract In several published studies, we have shown induction of immune tolerance to coagulations factors by hepatic gene transfer to animals with hemophilia. Tolerance induction is influenced by a number of complex factors, most notably T cell activation and induction of antigen-specific CD4+CD25+FoxP3+ regulatory T cells (Treg). We sought to better understand antigen presentation to CD4+ T cells and the dynamics of the resulting T cell response. To characterize the interaction of adeno-associated virus (AAV) antigen expression in the liver with immune cells, we used an AAV8 vector, which have a high tropism for murine liver, expressing cytoplasmic ovalbumin (AAV8-Cyto-Ova) from the EF1α promoter. Use of AAV8-Cyto-Ova allowed us to eliminate effects from systemic antigen delivery. Vector was injected into the tail vein of DO11.10-transgenic RAG-/- mice, which contain exclusively Ova-specific CD4+ T cells and lack Treg. AAV8-Cyto-Ova caused upregulation of the very early activation marker CD69 on the CD4+ T cells as early as 2 weeks after gene transfer, with induced Treg emerging at about 3 weeks. CD69+CD4+ T cells were first observed in greatest numbers in the liver and celiac lymph node (LN), one of the liver-draining LN. This T cell activation persisted for several weeks. To better define the sites of T cell activation, we used the compound FTY720, which is an agonist of sphingosine-1-phosphate receptors and prevents migration of lymphocytes but does not alter T cell function. Two weeks after AAV8-Cyto-Ova, FTY720 sequestered activated T cells mostly in the liver and celiac LN, when compared to other lymphoid organs, indicating that these are the initial sites of T cell activation. At the 3-week time point, there were fewer activated T cells in the liver and celiac LN in mice that received FTY720, while instead accumulating in the blood. Most likely, activated T cells were prevented from reentering the lymphoid organs from the circulation, where they were sequestered. We conclude that T cells are first activated by AAV8-Cyto-Ova in the liver and celiac LN after two weeks, where they subsequently egress into the circulation and re-enter lymphoid tissues, with many returning to the liver and celiac LN. FTY720 given at 2 weeks prevented the newly activated T cells from leaving the liver and celiac LN. These results strongly suggest that antigen presentation and CD4+ T cell activation occur first in the liver and celiac LN, beginning about 2 weeks after vector administration. Consistent with this conclusion, adoptively transferred Ova-specific CD4+ T cells proliferated first and to a much greater degree in the celiac LN of AAV8-Cyto-Ova transduced mice. Inactiviating Kupffer cells with gadolinium chloride significantly reduced antigen-specific proliferation, illustrating the requirement for professional resident liver antigen-presenting cells. Furthermore, we show that - in contrast to the AAV expression of secreted Ova - Treg are exclusively extrathymically induced after AAV8-Cyto-Ova vector administration. These Treg are found in high numbers in the blood after 2 weeks in mice given the FTY720 compound, suggesting that these peripherally induced Treg quickly enter the circulation. In conclusion, the liver and its draining celiac LN are key sites for antigen presentation and T cell activation in response to transgene expression directed by hepatic gene transfer. Presentation of antigen derived from a non-secreted transgene product induces FoxP3+ Treg that rapidly distribute through the circulation. Disclosures Herzog: Novo Nordisk: Research Funding; Spark Therapeutics: Patents & Royalties: Patent licenses.

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Acquisition and presentation of follicular dendritic cell–bound antigen by lymph node–resident dendritic cells

Journal of Experimental Medicine ◽

10.1084/jem.20100354 ◽

2010 ◽

Vol 208 (1) ◽

pp. 135-148 ◽

Cited By ~ 29

Author(s):

Megan L. McCloskey ◽

Maria A. Curotto de Lafaille ◽

Michael C. Carroll ◽

Adrian Erlebacher

Keyword(s):

Dendritic Cells ◽

Lymph Node ◽

T Cell ◽

Antigen Presentation ◽

T Cell Activation ◽

Immune Complexes ◽

Cell Activation ◽

Follicular Dendritic Cell ◽

Affinity Maturation ◽

Follicular Dendritic

Follicular dendritic cells (DCs [FDCs]) are prominent stromal cell constituents of B cell follicles with the remarkable ability to retain complement-fixed antigens on their cell surface for extended periods of time. These retained immune complexes have long been known to provide the antigenic stimulus that drives antibody affinity maturation, but their role in cellular immunity has remained unclear. In this study, we show that FDC-retained antigens are continually sampled by lymph node–resident DCs for presentation to CD8 T cells. This novel pathway of antigen acquisition was detectable when FDCs were loaded with purified antigens bound into classical antigen–antibody immune complexes, as well as after pregnancy, when they are loaded physiologically with antigens associated with the complement-fixed microparticles released from the placenta into maternal blood. In both cases, ensuing antigen presentation was profoundly tolerogenic, as it induced T cell deletion even under inflammatory conditions. These results significantly broaden the scope of FDC function and suggest new ways that the complement system and persistent antigen presentation might influence T cell activation and the maintenance of peripheral immune tolerance.

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