34 results found
Denton AE, Dooley J, Cinti I, et al., 2022, Targeting TLR4 during vaccination boosts MAdCAM-1+ lymphoid stromal cell activation and promotes the aged germinal center response, Science Immunology, Vol: 7, Pages: 1-17, ISSN: 2470-9468
The failure to generate enduring humoral immunity after vaccination is a hallmark of advancing age. This can be attributed to a reduction in the germinal center (GC) response, which generates long-lived antibody-secreting cells that protect against (re)infection. Despite intensive investigation, the primary cellular defect underlying impaired GCs in aging has not been identified. Here, we used heterochronic parabiosis to demonstrate that GC formation was dictated by the age of the lymph node (LN) microenvironment rather than the age of the immune cells. Lymphoid stromal cells are a key determinant of the LN microenvironment and are also an essential component underpinning GC structure and function. Using mouse models, we demonstrated that mucosal adressin cell adhesion molecule-1 (MAdCAM-1)-expressing lymphoid stromal cells were among the first cells to respond to NP-KLH + Alum immunization, proliferating and up-regulating cell surface proteins such as podoplanin and cell adhesion molecules. This response was essentially abrogated in aged mice. By targeting TLR4 using adjuvants, we improved the MAdCAM-1+ stromal cell response to immunization. This correlated with improved GC responses in both younger adult and aged mice, suggesting a link between stromal cell responses to immunization and GC initiation. Using bone marrow chimeras, we also found that MAdCAM-1+ stromal cells could respond directly to TLR4 ligands. Thus, the age-associated defect in GC and stromal cell responses to immunization can be targeted to improve vaccines in older people.
Linterman MA, Denton AE, 2021, Selenium saves ferroptotic TFH cells to fortify the germinal center, Nature Immunology, Vol: 22, Pages: 1074-1076, ISSN: 1529-2908
Inhibition of ferroptosis via selenium supplementation promotes the survival of follicular helper T cells, boosting the germinal center and antibody response following vaccination in mice and people.
Cinti I, Denton AE, 2021, Lymphoid Stromal cells - more than just a highway to humoral immunity, Oxford Open Immunology, Vol: 2, Pages: 1-12, ISSN: 2633-6960
The generation of high affinity long-lived antibody responses is dependent on the differentiation of plasma cells and memory B cells, which are themselves the product of the germinal centre (GC) response. The GC forms in secondary lymphoid organs in response to antigenic stimulation and is dependent on the coordinated interactions between many types of leucocytes. These leucocytes are brought together on an interconnected network of specialised lymphoid stromal cells, which provide physical and chemical guidance to immune cells that are essential for the GC response. In this review we will highlight recent advancements in lymphoid stromal cell immunobiology and their role in regulating the GC, and discuss the contribution of lymphoid stromal cells to age-associated immunosenescence.
Biram A, Winter E, Denton AE, et al., 2020, B cell diversification Is uncoupled from SAP-mediated selection forces in chronic germinal centers within Peyer's patches, Cell Reports, Vol: 30, Pages: 1910-1922.e5, ISSN: 2211-1247
Antibodies secreted within the intestinal tract provide protection from the invasion of microbes into the host tissues. Germinal center (GC) formation in lymph nodes and spleen strictly requires SLAM-associated protein (SAP)-mediated T cell functions; however, it is not known whether this mechanism plays a similar role in mucosal-associated lymphoid tissues. Here, we find that in Peyer's patches (PPs), SAP-mediated T cell help is required for promoting B cell selection in GCs, but not for clonal diversification. PPs of SAP-deficient mice host chronic GCs that are absent in T cell-deficient mice. GC B cells in SAP-deficient mice express AID and Bcl6 and generate plasma cells in proportion to the GC size. Single-cell IgA sequencing analysis reveals that these mice host few diversified clones that were subjected to mild selection forces. These findings demonstrate that T cell-derived help to B cells in PPs includes SAP-dependent and SAP-independent functions.
Vanderleyden I, Fra-Bido SC, Innocentin S, et al., 2020, Follicular regulatory T cells can access the germinal center independently of CXCR5, Cell Reports, Vol: 30, Pages: 611-619.e4, ISSN: 2211-1247
The germinal center (GC) response is critical for generating high-affinity humoral immunity and immunological memory, which forms the basis of successful immunization. Control of the GC response is thought to require follicular regulatory T (Tfr) cells, a subset of suppressive Foxp3+ regulatory T cells located within GCs. Relatively little is known about the exact role of Tfr cells within the GC and how they exert their suppressive function. A unique feature of Tfr cells is their reported CXCR5-dependent localization to the GC. Here, we show that the lack of CXCR5 on Foxp3+ regulatory T cells results in a reduced frequency, but not an absence, of GC-localized Tfr cells. This reduction in Tfr cells is not sufficient to alter the magnitude or output of the GC response. This demonstrates that additional, CXCR5-independent mechanisms facilitate Treg cell homing to the GC.
Denton AE, Carr EJ, Magiera LP, et al., 2019, Embryonic FAP(+) lymphoid tissue organizer cells generate the reticular network of adult lymph nodes, Journal of Experimental Medicine, Vol: 216, Pages: 2242-2252, ISSN: 0022-1007
The induction of adaptive immunity is dependent on the structural organization of LNs, which is in turn governed by the stromal cells that underpin LN architecture. Using a novel fate-mapping mouse model, we trace the developmental origin of mesenchymal LN stromal cells (mLNSCs) to a previously undescribed embryonic fibroblast activation protein-α (FAP)+ progenitor. FAP+ cells of the LN anlagen express lymphotoxin β receptor (LTβR) and vascular cell adhesion molecule (VCAM), but not intercellular adhesion molecule (ICAM), suggesting they are early mesenchymal lymphoid tissue organizer (mLTo) cells. Clonal labeling shows that FAP+ progenitors locally differentiate into mLNSCs. This process is also coopted in nonlymphoid tissues in response to infection to facilitate the development of tertiary lymphoid structures, thereby mimicking the process of LN ontogeny in response to infection.
Hesketh RL, Wang J, Wright AJ, et al., 2019, Magnetic Resonance Imaging Is More Sensitive Than PET for Detecting Treatment-Induced Cell Death-Dependent Changes in Glycolysis, CANCER RESEARCH, Vol: 79, Pages: 3557-3569, ISSN: 0008-5472
Espeli M, Bashford-Rogers R, Sowerby JM, et al., 2019, Fc gamma RIIb differentially regulates pre-immune and germinal center B cell tolerance in mouse and human, Nature Communications, Vol: 10, Pages: 1-14, ISSN: 2041-1723
Several tolerance checkpoints exist throughout B cell development to control autoreactive B cells and prevent the generation of pathogenic autoantibodies. FcγRIIb is an Fc receptor that inhibits B cell activation and, if defective, is associated with autoimmune disease, yet its impact on specific B cell tolerance checkpoints is unknown. Here we show that reduced expression of FcγRIIb enhances the deletion and anergy of autoreactive immature B cells, but in contrast promotes autoreactive B cell expansion in the germinal center and serum autoantibody production, even in response to exogenous, non-self antigens. Our data thus show that FcγRIIb has opposing effects on pre-immune and post-immune tolerance checkpoints, and suggest that B cell tolerance requires the control of bystander germinal center B cells with low or no affinity for the immunizing antigen.
Denton AE, Innocentin S, Carr EJ, et al., 2019, Type I interferon induces CXCL13 to support ectopic germinal center formation, Journal of Experimental Medicine, Vol: 216, Pages: 621-637, ISSN: 0022-1007
Ectopic lymphoid structures form in a wide range of inflammatory conditions, including infection, autoimmune disease, and cancer. In the context of infection, this response can be beneficial for the host: influenza A virus infection–induced pulmonary ectopic germinal centers give rise to more broadly cross-reactive antibody responses, thereby generating cross-strain protection. However, despite the ubiquity of ectopic lymphoid structures and their role in both health and disease, little is known about the mechanisms by which inflammation is able to convert a peripheral tissue into one that resembles a secondary lymphoid organ. Here, we show that type I IFN produced after viral infection can induce CXCL13 expression in a phenotypically distinct population of lung fibroblasts, driving CXCR5-dependent recruitment of B cells and initiating ectopic germinal center formation. This identifies type I IFN as a novel inducer of CXCL13, which, in combination with other stimuli, can promote lung remodeling, converting a nonlymphoid tissue into one permissive to functional tertiary lymphoid structure formation.
van Nieuwenhuijze A, Burton O, Lemaitre P, et al., 2018, Mice deficient in nucleoporin nup210 develop peripheral T cell alterations, Frontiers in Immunology, Vol: 9, Pages: 1-13, ISSN: 1664-3224
The nucleopore is an essential structure of the eukaryotic cell, regulating passage between the nucleus and cytoplasm. While individual functions of core nucleopore proteins have been identified, the role of other components, such as Nup210, are poorly defined. Here, through the use of an unbiased ENU mutagenesis screen for mutations effecting the peripheral T cell compartment, we identified a Nup210 mutation in a mouse strain with altered CD4/CD8 T cell ratios. Through the generation of Nup210 knockout mice we identified Nup210 as having a T cell-intrinsic function in the peripheral homeostasis of T cells. Remarkably, despite the deep evolutionary conservation of this key nucleopore complex member, no other major phenotypes developed, with viable and healthy knockout mice. These results identify Nup210 as an important nucleopore complex component for peripheral T cells, and raise further questions of why this nucleopore component shows deep evolutionary conservation despite seemingly redundant functions in most cell types.
Denton AE, Roberts EW, Fearon DT, 2018, Stromal Cells in the Tumor Microenvironment, STROMAL IMMUNOLOGY, Editors: Owens, Lakins, Publisher: SPRINGER INTERNATIONAL PUBLISHING AG, Pages: 99-114, ISBN: 978-3-319-78125-9
Quinn KM, Kan W-T, Watson KA, et al., 2017, Extrinsically derived TNF is primarily responsible for limiting antiviral CD8+T cell response magnitude, PLoS One, Vol: 12, Pages: 1-13, ISSN: 1932-6203
TNF is a pro-inflammatory cytokine produced by both lymphoid and non-lymphoid cells. As a consequence of the widespread expression of its receptors (TNFR1 and 2), TNF plays a role in many important biological processes. In the context of influenza A virus (IAV) infection, TNF has variably been implicated in mediating immunopathology as well as suppression of the immune response. Although a number of cell types are able to produce TNF, the ability of CD8+ T cells to produce TNF following viral infection is a hallmark of their effector function. As such, the regulation and role of CD8+ T cell-derived TNF following viral infection is of great interest. Here, we show that the biphasic production of TNF by CD8+ T cells following in vitro stimulation corresponds to distinct patterns of epigenetic modifications. Further, we show that a global loss of TNF during IAV infection results in an augmentation of the peripheral virus-specific CD8+ T cell response. Subsequent adoptive transfer experiments demonstrated that this attenuation of the CD8+ T cell response was largely, but not exclusively, conferred by extrinsic TNF, with intrinsically-derived TNF making only modest contributions. In conclusion, TNF exerts an immunoregulatory role on CD8+ T cell responses following IAV infection, an effect that is largely mediated by extrinsically-derived TNF.
Denton AE, Carr E, Pierson W, et al., 2017, CXCL13 modulates B cell trafficking into the lung early during influenza A virus infection and initiates tertiary lymphoid organ formation, Publisher: E M H SWISS MEDICAL PUBLISHERS LTD, Pages: 74S-74S, ISSN: 1424-7860
Denton AE, Linterman MA, 2017, Stromal networking: cellular connections in the germinal centre, CURRENT OPINION IN IMMUNOLOGY, Vol: 45, Pages: 103-111, ISSN: 0952-7915
Croft AP, Campos J, Nayar S, et al., 2017, IDENTIFICATION OF A NOVEL SUBSET OF PATHOGENIC STROMAL CELLS WITH KEY EFFECTOR FUNCTIONS IN TISSUE INFLAMMATION AND DAMAGE, 37th European Workshop on Rheumatology Research (EWRR), Publisher: BMJ PUBLISHING GROUP, Pages: A51-A51, ISSN: 0003-4967
Flint TR, Janowitz T, Connell CM, et al., 2016, Tumor-induced IL-6 reprograms host metabolism to suppress anti-tumor immunity, Cell Metabolism, Vol: 24, Pages: 672-684, ISSN: 1550-4131
In patients with cancer, the wasting syndrome, cachexia, is associated with caloric deficiency. Here, we describe tumor-induced alterations of the host metabolic response to caloric deficiency that cause intratumoral immune suppression. In pre-cachectic mice with transplanted colorectal cancer or autochthonous pancreatic ductal adenocarcinoma (PDA), we find that IL-6 reduces the hepatic ketogenic potential through suppression of PPARalpha, the transcriptional master regulator of ketogenesis. When these mice are challenged with caloric deficiency, the resulting relative hypoketonemia triggers a marked rise in glucocorticoid levels. Multiple intratumoral immune pathways are suppressed by this hormonal stress response. Moreover, administering corticosterone to elevate plasma corticosterone to a level that is lower than that occurring in cachectic mice abolishes the response of mouse PDA to an immunotherapy that has advanced to clinical trials. Therefore, tumor-induced IL-6 impairs the ketogenic response to reduced caloric intake, resulting in a systemic metabolic stress response that blocks anti-cancer immunotherapy.
Campos J, Nayar S, Croft AP, et al., 2016, DEPLETION OF LYMPHOID-LIKE STROMAL CELLS IMPAIRS TERTIARY LYMPHOID ORGAN FORMATION IN AN ANIMAL MODEL OF SJOGREN'S SYNDROME, Annual European Congress of Rheumatology (EULAR), Publisher: BMJ PUBLISHING GROUP, Pages: 945-945, ISSN: 0003-4967
Roberts EW, Denton AE, Fearon DT, 2016, Roles of Stromal Cells in the Immune System, Encyclopedia of Cell Biology, Pages: 616-623, ISBN: 9780123947963
Stromal cells were typically defined as passive organizers of an organ, producing extracellular matrix and basement membrane proteins. While stromal cells do provide important structural support for most organs, their role in coordinating the local microenvironment in the steady state and during inflammation is becoming increasingly better known. In this article we will review the many roles of stromal cells in regulating immune responses in their local tissue environment, including both lymphoid tissue and inflammatory lesions.
Russ BE, Olshanksy M, Smallwood HS, et al., 2014, Distinct Epigenetic Signatures Delineate Transcriptional Programs during Virus-Specific CD8(+) T Cell Differentiation (vol 41, pg 853, 2014), IMMUNITY, Vol: 41, Pages: 1064-1064, ISSN: 1074-7613
Linterman MA, Denton AE, 2014, Treg Cells and CTLA-4: The Ball and Chain of the Germinal Center Response, IMMUNITY, Vol: 41, Pages: 876-878, ISSN: 1074-7613
Linterman MA, Denton AE, Clare S, et al., 2014, CD28 expression is required after T cell priming for helper T cell responses and protective immunity to infection, Publisher: WILEY-BLACKWELL, Pages: 63-63, ISSN: 0019-2805
Denton AE, Roberts EW, Linterman MA, et al., 2014, Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8+T cells, Publisher: WILEY-BLACKWELL, Pages: 64-64, ISSN: 0019-2805
Russ BE, Olshanksy M, Smallwood HS, et al., 2014, Distinct Epigenetic Signatures Delineate Transcriptional Programs during Virus-Specific CD8(+) T Cell Differentiation, IMMUNITY, Vol: 41, Pages: 853-865, ISSN: 1074-7613
Linterman MA, Denton AE, Divekar DP, et al., 2014, CD28 expression is required after T cell priming for helper T cell responses and protective immunity to infection, eLife, Vol: 3, Pages: 1-31, ISSN: 2050-084X
The co-stimulatory molecule CD28 is essential for activation of helper T cells. Despitethis critical role, it is not known whether CD28 has functions in maintaining T cell responsesfollowing activation. To determine the role for CD28 after T cell priming, we generated a strainof mice where CD28 is removed from CD4+ T cells after priming. We show that continued CD28expression is important for effector CD4+ T cells following infection; maintained CD28 is requiredfor the expansion of T helper type 1 cells, and for the differentiation and maintenance of T follicularhelper cells during viral infection. Persistent CD28 is also required for clearance of the bacteriumCitrobacter rodentium from the gastrointestinal tract. Together, this study demonstrates that CD28persistence is required for helper T cell polarization in response to infection, describing a novelfunction for CD28 that is distinct from its role in T cell priming.
Linterman MA, Denton AE, Divekar DP, et al., 2014, CD28 Expression is Required after T Cell Priming for Follicular Helper T Cell Responses and Protective Immunity to Infection, 18th Germinal Centre Conference, Publisher: WILEY-BLACKWELL, Pages: 224-224, ISSN: 0300-9475
Denton AE, Roberts EW, Linterman MA, et al., 2014, Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8(+) T cells, Proceedings of the National Academy of Sciences of the United States of America, Vol: 111, Pages: 12139-12144, ISSN: 0027-8424
Fibroblastic reticular cells (FRCs), through their expression of CC chemokine ligand (CCL)19 and CCL21, attract and retain T cells in lymph nodes (LNs), but whether this function applies to both resting and activated T cells has not been examined. Here we describe a model for conditionally depleting FRCs from LNs based on their expression of the diphtheria toxin receptor (DTR) directed by the gene encoding fibroblast activation protein-α (FAP). As expected, depleting FAP+ FRCs causes the loss of naïve T cells, B cells, and dendritic cells from LNs, and this loss decreases the magnitude of the B- and T-cell responses to a subsequent infection with influenza A virus. In contrast, depleting FAP+ FRCs during an ongoing influenza infection does not diminish the number or continued response of activated T and B cells in the draining LNs, despite still resulting in the loss of naïve T cells. Therefore, different rules govern the LN trafficking of resting and activated T cells; once a T cell is engaged in antigen-specific clonal expansion, its retention no longer depends on FRCs or their chemokines, CCL19 and CCL21. Our findings suggest that activated T cells remain in the LN because they down-regulate the expression of the sphingosine-1 phosphate receptor-1, which mediates the exit of lymphocytes from secondary lymphoid organs. Therefore, LN retention of naïve lymphocytes and the initiation of an immune response depend on FRCs, but is an FRC independent and possibly cell-autonomous response of activated T cells, which allows the magnitude of clonal expansion to determine LN egress.
Roberts EW, Deonarine A, Jones JO, et al., 2013, Depletion of stromal cells expressing fibroblast activation protein-alpha from skeletal muscle and bone marrow results in cachexia and anemia, Journal of Experimental Medicine, Vol: 210, Pages: 1137-1151, ISSN: 0022-1007
Fibroblast activation protein-α (FAP) identifies stromal cells of mesenchymal origin in human cancers and chronic inflammatory lesions. In mouse models of cancer, they have been shown to be immune suppressive, but studies of their occurrence and function in normal tissues have been limited. With a transgenic mouse line permitting the bioluminescent imaging of FAP+ cells, we find that they reside in most tissues of the adult mouse. FAP+ cells from three sites, skeletal muscle, adipose tissue, and pancreas, have highly similar transcriptomes, suggesting a shared lineage. FAP+ cells of skeletal muscle are the major local source of follistatin, and in bone marrow they express Cxcl12 and KitL. Experimental ablation of these cells causes loss of muscle mass and a reduction of B-lymphopoiesis and erythropoiesis, revealing their essential functions in maintaining normal muscle mass and hematopoiesis, respectively. Remarkably, these cells are altered at these sites in transplantable and spontaneous mouse models of cancer-induced cachexia and anemia. Thus, the FAP+ stromal cell may have roles in two adverse consequences of cancer: their acquisition by tumors may cause failure of immunosurveillance, and their alteration in normal tissues contributes to the paraneoplastic syndromes of cachexia and anemia.
Russ BE, Denton AE, Hatton L, et al., 2012, Defining the molecular blueprint that drives CD8(+) T cell differentiation in response to infection, Frontiers in Immunology, Vol: 3, ISSN: 1664-3224
A cardinal feature of adaptive, cytotoxic T lymphocyte (CTL)-mediated immunity is the ability of naïve CTLs to undergo a program of differentiation and proliferation upon activation resulting in the acquisition of lineage-specific T cell functions and eventual establishment of immunological memory. In this review, we examine the molecular factors that shape both the acquisition and maintenance of lineage-specific effector function in virus-specific CTL during both the effector and memory phases of immunity.
Denton AE, Wesselingh R, Gras S, et al., 2011, Affinity Thresholds for Naive CD8(+) CTL Activation by Peptides and Engineered Influenza A Viruses, JOURNAL OF IMMUNOLOGY, Vol: 187, Pages: 5733-5744, ISSN: 0022-1767
Denton AE, Russ BE, Doherty PC, et al., 2011, Differentiation-dependent functional and epigenetic landscapes for cytokine genes in virus-specific CD8(+) T cells, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 108, Pages: 15306-15311, ISSN: 0027-8424
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