scholarly journals The thymus and the science of self

2021 ◽  
Author(s):  
Vincent Geenen
Keyword(s):  
T Cells ◽  
Adaptive Immune System ◽  
Lymphoid Organ ◽  
The Body ◽  
Effector Cells ◽  
Major Organ ◽  
Organ Specific ◽  
Health And Disease ◽  
Essential State ◽  
The 1960S

AbstractThe conventional perception asserts that immunology is the science of ‘discrimination’ between self and non-self. This concept is however no longer tenable as effector cells of the adaptive immune system are first conditioned to be tolerant to the body’s own antigens, collectively known as self until now. Only then attain these effectors the responsiveness to non-self. The acquisition of this essential state of tolerance to self occurs for T cells in the thymus, the last major organ of our body that revealed its intricate function in health and disease. The ‘thymus’ as an anatomical notion was first notably documented in Ancient Greece although our present understanding of the organ’s functions was only deciphered commencing in the 1960s. In the late 1980s, the thymus was identified as the site where clones of cells reactive to self, termed ‘forbidden’ thymocytes, are physically depleted as the result of a process now known as negative selection. The recognition of this mechanism further contributed to the belief that the central rationale of immunology as a science lies in the distinction between self and non-self. This review will discuss the evidence that the thymus serves as a unique lymphoid organ able to instruct T cells to recognize and be tolerant to harmless self before adopting the capacity to defend the body against potentially injurious non-self-antigens presented in the context of different challenges from infections to exposure to malignant cells. The emerging insight into the thymus’ cardinal functions now also provides an opportunity to exploit this knowledge to develop novel strategies that specifically prevent or even treat organ-specific autoimmune diseases.

scholarly journals Human Dendritic Cells: Ontogeny and Their Subsets in Health and Disease

2018 ◽  
Vol 6 (4) ◽  
pp. 88 ◽  
Author(s):  
Sandra Solano-Gálvez ◽  
Sonia Tovar-Torres ◽  
María Tron-Gómez ◽  
Ariane Weiser-Smeke ◽  
Diego Álvarez-Hernández ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Current Knowledge ◽  
Lymphoid Organ ◽  
Heterogeneous Population ◽  
Health And Disease ◽  
Human Dendritic Cells ◽  
Activation Status

Dendritic cells (DCs) are a type of cells derived from bone marrow that represent 1% or less of the total hematopoietic cells of any lymphoid organ or of the total cell count of the blood or epithelia. Dendritic cells comprise a heterogeneous population of cells localized in different tissues where they act as sentinels continuously capturing antigens to present them to T cells. Dendritic cells are uniquely capable of attracting and activating naïve CD4+ and CD8+ T cells to initiate and modulate primary immune responses. They have the ability to coordinate tolerance or immunity depending on their activation status, which is why they are also considered as the orchestrating cells of the immune response. The purpose of this review is to provide a general overview of the current knowledge on ontogeny and subsets of human dendritic cells as well as their function and different biological roles.

scholarly journals Regulation of T cell expansion by antigen presentation dynamics

2019 ◽  
Vol 116 (13) ◽  
pp. 5914-5919 ◽  
Author(s):  
Andreas Mayer ◽  
Yaojun Zhang ◽  
Alan S. Perelson ◽  
Ned S. Wingreen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Expansion ◽  
Essential Feature ◽  
Adaptive Immune Response ◽  
Adaptive Immune System ◽  
Effective Response ◽  
Effector Cells ◽  
Adaptive Immune ◽  
T Cell Expansion

An essential feature of the adaptive immune system is the proliferation of antigen-specific lymphocytes during an immune reaction to form a large pool of effector cells. This proliferation must be regulated to ensure an effective response to infection while avoiding immunopathology. Recent experiments in mice have demonstrated that the expansion of a specific clone of T cells in response to cognate antigen obeys a striking inverse power law with respect to the initial number of T cells. Here, we show that such a relationship arises naturally from a model in which T cell expansion is limited by decaying levels of presented antigen. The same model also accounts for the observed dependence of T cell expansion on affinity for antigen and on the kinetics of antigen administration. Extending the model to address expansion of multiple T cell clones competing for antigen, we find that higher-affinity clones can suppress the proliferation of lower-affinity clones, thereby promoting the specificity of the response. Using the model to derive optimal vaccination protocols, we find that exponentially increasing antigen doses can achieve a nearly optimized response. We thus conclude that the dynamics of presented antigen is a key regulator of both the size and specificity of the adaptive immune response.

scholarly journals Regulation of T cell expansion by antigen presentation dynamics

2018 ◽  
Author(s):  
Andreas Mayer ◽  
Yaojun Zhang ◽  
Alan S. Perelson ◽  
Ned S. Wingreen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Expansion ◽  
Essential Feature ◽  
Adaptive Immune Response ◽  
Adaptive Immune System ◽  
Effective Response ◽  
Effector Cells ◽  
Adaptive Immune ◽  
T Cell Expansion

An essential feature of the adaptive immune system is the proliferation of antigen-specific lymphocytes during an immune reaction to form a large pool of effector cells. This proliferation must be regulated to ensure an effective response to infection while avoiding immunopathology. Recent experiments in mice have demonstrated that the expansion of a specific clone of T cells in response to cognate antigen obeys a striking inverse power law with respect to the initial number of T cells. Here, we show that such a relationship arises naturally from a model in which T cell expansion is limited by decaying levels of presented antigen. The same model also accounts for the observed dependence of T cell expansion on affinity for antigen and on the kinetics of antigen administration. Extending the model to address expansion of multiple T cell clones competing for antigen, we find that higher affinity clones can suppress the proliferation of lower affinity clones, thereby promoting the specificity of the response. Employing the model to derive optimal vaccination protocols, we find that exponentially increasing antigen doses can achieve a nearly optimized response. We thus conclude that the dynamics of presented antigen is a key regulator of both the size and specificity of the adaptive immune response.

scholarly journals Study on cellular events in postthymectomy autoimmune oophoritis in mice. I. Requirement of Lyt-1 effector cells for oocytes damage after adoptive transfer.

1982 ◽  
Vol 156 (6) ◽  
pp. 1565-1576 ◽  
Author(s):  
S Sakaguchi ◽  
T Takahashi ◽  
Y Nishizuka
Keyword(s):  
T Cells ◽  
Adoptive Transfer ◽  
Delayed Type Hypersensitivity ◽  
Effector Cells ◽  
Period 2 ◽  
Cyclophosphamide Treatment ◽  
Organ Specific ◽  
Circulating Autoantibodies ◽  
Autoimmune Oophoritis

Neonatal thymectomy during the critical period, 2-4 d after birth, can induce various organ-specific autoimmune diseases including oophoritis in A/J mice. The oophoritis thus induced was passively transferred into neonatal mice by injection of spleen cells obtained from syngeneic donors with the disease. Recipient ovaries were rapidly damaged with remarkable mononuclear cell infiltration and destruction of follicular structures. The phenotype of effector cells responsible for successful adoptive transfer was found to be Thy-1+, Lyt-1+,23-, Ia-, Qa-1-, and was sensitive to antithymocyte serum treatment but resistant to cyclophosphamide treatment or in vitro X-ray irradiation. The compatibility between donor and recipient at the major histocompatibility complex was not required for the effector phase of transfer. The oophoritis induced in BALB/c (nu/+ or +/+) was also shown to be transferred into athymic BALB/c nude mice with resulting ovarian lesion and circulating autoantibodies against oocytes. In this transfer system, the effector cells were also demonstrated to be T cells with the Lyt-1+,23- phenotype. Adoptive transfer experiments in both systems revealed that the destruction of ovaries in postthymectomy autoimmune oophoritis was mediated by Lyt-1 T cells. Whether these T cells can be distinguished from other Lyt-1 cells, such as T helper cells and effector T cells in delayed-type hypersensitivity (DTH), is not clear at present, but the results suggest that the effector mechanisms may be closely related to a DTH reaction.

scholarly journals Interleukin-22 Influences the Th1/Th17 Axis

2021 ◽  
Vol 12 ◽  
Author(s):  
Hannes Lindahl ◽  
Tomas Olsson
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Inflammatory Diseases ◽  
Adaptive Immune System ◽  
Cell Polarization ◽  
The Body ◽  
Innate Immune ◽  
Interleukin 22 ◽  
Downstream Effects ◽  
Wide Range

Interleukin-22 (IL-22) is secreted by a wide range of immune cells and its downstream effects are mediated by the IL-22 receptor, which is present on non-immune cells in many organs throughout the body. IL-22 is an inflammatory mediator that conditions the tissue compartment by upregulating innate immune responses and is also a homeostatic factor that promotes tissue integrity and regeneration. Interestingly, the IL-22 system has also been linked to many T cell driven inflammatory diseases. Despite this, the downstream effects of IL-22 on the adaptive immune system has received little attention. We have reviewed the literature for experimental data that suggest IL-22 mediated effects on T cells, either transduced directly or via mediators expressed by innate immune cells or non-immune cells in response to IL-22. Collectively, the reviewed data indicate that IL-22 has a hitherto unappreciated influence on T helper cell polarization, or the secretion of signature cytokines, that is context dependent but in many cases results in a reduction of the Th1 type response and to some extent promotion of regulatory T cells. Further studies are needed that specifically address these aspects of IL-22 signaling, which can benefit the understanding and treatment of a wide range of diseases.

Modulation of T cell and macrophage tumor infiltration by the TLR9 agonist lefitolimod in a murine model of colorectal cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 687-687
Author(s):  
Manuel Schmidt ◽  
Detlef Oswald ◽  
Barbara Volz ◽  
Burghardt Wittig ◽  
Kerstin Kapp
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Immune Surveillance ◽  
Adaptive Immune System ◽  
Intratumoral Injection ◽  
Effector Cells ◽  
T Cell Infiltration

687 Background: The use of TLR9 agonists for immunotherapeutic approaches is supported by preclinical and ongoing clinical studies. Lefitolimod, a covalently-closed dumbbell-shaped DNA construct, is an immune surveillance reactivator which broadly activates cells of the innate and adaptive immune system. The conversion of non-immunogenic (cold) tumors into immunogenic (hot) tumors, characterized by their T-cell infiltration, is a pre-requisite for response to immunotherapies. By its mode-of-action lefitolimod likely provides the necessary signals for activation of immune cells and their differentiation into anti-tumor effector cells as well as their recruitment to the tumor microenvironment (TME). Methods: To support the further clinical development of lefitolimod in mCRC, the syngeneic colon carcinoma model CT26 was used to evaluate anti-tumoral efficacy of lefitolimod and its modulation of the TME. The phenotype of T cells and macrophages present within tumor-infiltrating immune cells were analyzed by flow cytometry. Their localization within the tumor was investigated by immunohistochemistry. Results: Intratumoral injection of single-agent lefitolimod in the CT26 model resulted in reduced tumor growth. This was accompanied by an increased infiltration of T cells, in particular CD8+ T cells, into the tumor center. The CD8+ T cells were activated and showed an up-regulation of the cytolytic effector Granzyme B. Correspondingly, the ratio of activated CD8+ T cells with cytolytic function to regulatory T cells was increased by lefitolimod. Moreover, lefitolimod led to the recruitment of macrophages into the tumor and, importantly, an increase of M1 macrophages and a decrease of M2 macrophages inside the TME. Conclusions: Lefitolimod treatment resulted in modulation of the TME towards an increase of effector cells with anti-tumoral functions like cytotoxic CD8+ T cells and M1-type macrophages as well as a decrease of pro-tumoral M2-type macrophages. Therefore, lefitolimod provides the essential requirements for clinical response to immunotherapeutic drugs like checkpoint inhibitors. This predestines lefitolimod as combination partner in immuno-oncological trials.

scholarly journals Modes of Communication between T Cells and Relevance for Immune Responses

2020 ◽  
Vol 21 (8) ◽  
pp. 2674 ◽  
Author(s):  
Lion F. K. Uhl ◽  
Audrey Gérard
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adaptive Immune System ◽  
T Cell Response ◽  
The Body ◽  
Overall Response ◽  
Physiological Relevance ◽  
Self Tolerance ◽  
Global Coordination ◽  
The Individual

T cells are essential mediators of the adaptive immune system, which constantly patrol the body in search for invading pathogens. During an infection, T cells that recognise the pathogen are recruited, expand and differentiate into subtypes tailored to the infection. In addition, they differentiate into subsets required for short and long-term control of the pathogen, i.e., effector or memory. T cells have a remarkable degree of plasticity and heterogeneity in their response, however, their overall response to a given infection is consistent and robust. Much research has focused on how individual T cells are activated and programmed. However, in order to achieve a critical level of population-wide reproducibility and robustness, neighbouring cells and surrounding tissues have to provide or amplify relevant signals to tune the overall response accordingly. The characteristics of the immune response—stochastic on the individual cell level, robust on the global level—necessitate coordinated responses on a system-wide level, which facilitates the control of pathogens, while maintaining self-tolerance. This global coordination can only be achieved by constant cellular communication between responding cells, and faults in this intercellular crosstalk can potentially lead to immunopathology or autoimmunity. In this review, we will discuss how T cells mount a global, collective response, by describing the modes of T cell-T cell (T-T) communication they use and highlighting their physiological relevance in programming and controlling the T cell response.

scholarly journals Basic concepts in clinical immunology: A review

2021 ◽  
Vol 12 (3) ◽  
pp. 490-496
Author(s):  
Andrew Nakibinge Kiboneka
Keyword(s):  
Immune System ◽  
Blood Cells ◽  
White Blood Cells ◽  
Adaptive Immune System ◽  
The Body ◽  
Molecular Structures ◽  
Natural Immunity ◽  
Hematopoietic Stem ◽  
Effector Cells ◽  
Infection Pattern

Immunity is the state of protection against foreign pathogens or substances(antigens). Host defence mechanisms consist of innate immunity (natural immunity), which mediates the initial protection against infections, and adaptive immunity (specific/acquired immunity), which develops more slowly and provides more specialized and more effective defence against infections. The immune system evolved to protect multicellular organisms against pathogens. The body is protected against pathogens by a variety of effector cells and molecules that together make up the immune system. All the cellular elements of blood, including the red blood cells, platelets and white blood cells of the immune system, ultimately derive from the hematopoietic stem cells of the bone marrow. The cells of the adaptive immune system consist of lymphocytes, antigen-presenting cells and effector cells that eliminate microbes. Strategies of avoidance, and tolerance represent different ways of dealing with pathogens. Anatomic barriers and chemical barriers e.g complement and antimicrobial proteins may be considered as primary forms of avoidance.Macrophages,neutrophils and dendritic cells are important cells that that detect infection. Pattern recognition receptors (PRRs) recognize simple molecules and regular patterns of molecular structures called pathogen associated molecular patterns. Some PRR are transmembrane proteins e.g Toll like receptors (TLRs). Vaccination is a simple, safe, and effective way of protecting people against harmful diseases, before they come into contact with them. Immunization is the process whereby a person is made immune or resistant to an infectious disease, typically by the administration of a vaccine. Inappropriate immune responses can result into hypersensitivity, autoimmune disease or immune deficiency.

scholarly journals Multiplex immunohistochemistry differences between Q fever and atherosclerotic abdominal aortic aneurysms indicate immune suppression

2021 ◽  
Author(s):  
Kimberley R.G. Cortenbach ◽  
Alexander H.J. Staal ◽  
Teske Schoffelen ◽  
Mark A.J. Gorris ◽  
Lieke L. Van der Woude ◽  
...  
Keyword(s):  
T Cells ◽  
Q Fever ◽  
Cytotoxic T Cells ◽  
Adaptive Immune System ◽  
Research Area ◽  
Aortic Aneurysms ◽  
Aortic Tissue ◽  
Local Inflammation ◽  
Effector Cells ◽  
Abdominal Aortic

Background: Chronic Q fever is a zoonosis caused by the bacterium Coxiella burnetii which can manifest as infection of an abdominal aortic aneurysm (AAA). Antibiotic therapy often fails, resulting in severe morbidity and high mortality. Whereas previous studies have focused on inflammatory processes in blood, the aim of this study was to investigate local inflammation in aortic tissue. Methods: Multiplex immunohistochemistry was used to investigate local inflammation in Q fever AAAs compared to atherosclerotic AAAs in aorta tissue specimen. Two six-plex panels were used to study both the innate and adaptive immune system. Results: Q fever AAAs and atherosclerotic AAAs contained similar numbers of CD68+ macrophages and CD3+ T cells. However, in Q fever AAAs the number of CD68+CD206+ M2 macrophages was increased, while expression of GM-CSF was decreased compared to atherosclerotic AAAs. Furthermore, Q fever AAAs showed an increase in both the number of CD8+ cytotoxic T cells and CD3+FoxP3+ regulatory T cells. Lastly, Q fever AAAs did not contain any well-defined granulomas. Conclusions: These findings demonstrate that despite the presence of pro-inflammatory effector cells, there is an immune suppressive micro environment in Q fever AAA resulting in persistent local infection with C. burnetii. Funding: This work was supported by SCAN consortium: European Research Area - CardioVascualar Diseases (ERA-CVD) grant [JTC2017-044] and TTW-NWO open technology grant [STW-14716].

scholarly journals The Teleost Thymus in Health and Disease: New Insights from Transcriptomic and Histopathological Analyses of Turbot, Scophthalmus maximus

Biology ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 221
Author(s):  
Paolo Ronza ◽  
Diego Robledo ◽  
Ana Paula Losada ◽  
Roberto Bermúdez ◽  
Belén G. Pardo ◽  
...  
Keyword(s):  
Adaptive Immune System ◽  
Scophthalmus Maximus ◽  
Infected Fish ◽  
Lymphoid Organ ◽  
Thymic Function ◽  
Pathological Conditions ◽  
Myxozoan Parasite ◽  
Health And Disease ◽  
Turbot Scophthalmus Maximus

The thymus is a primary lymphoid organ that plays a pivotal role in the adaptive immune system. The immunobiology of the thymus in fish is considered to be similar to that of mammals, but it is actually poorly characterized in several cultured teleost species. In particular, while investigations in human and veterinary medicine have highlighted that the thymus can be affected by different pathological conditions, little is known about its response during disease in fish. To better understand the role of the thymus under physiological and pathological conditions, we conducted a study in turbot (Scophthalmus maximus), a commercially valuable flatfish species, combining transcriptomic and histopathological analyses. The myxozoan parasite Enteromyxum scophthalmi, which represents a major challenge to turbot production, was used as a model of infection. The thymus tissues of healthy fish showed overrepresented functions related to its immunological role in T-cell development and maturation. Large differences were observed between the transcriptomes of control and severely infected fish. Evidence of inflammatory response, apoptosis modulation, and declined thymic function associated with loss of cellularity was revealed by both genomic and morphopathological analyses. This study presents the first description of the turbot thymus transcriptome and provides novel insights into the role of this organ in teleosts’ immune responses.

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