T cell subsets and their functions pdf
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- Genetic control of T-Cell subset representation in inbred mice
- Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections
- Differentiation and Function of T Cell Subsets in Infectious Diseases
- Genetic control of T-Cell subset representation in inbred mice
Infectious diseases remain a public health problem in the world, regardless of the continued effort at control. The aim of the host immune response during infection is to clear invading pathogens with limited tissue damage. Both innate and adaptive T cells play a key role in direct pathogen clearance through proinflammatory cytokine and cytotoxic T lymphocyte CTL activity.
Genetic control of T-Cell subset representation in inbred mice
The role of T cell subsets and cytokines in the regulation of intracellular bacterial infection. Oliveira 1 , J. Harms 2 , E. Rech 3 , R. Rodarte 3 , A. Bocca 3 , A. Goes 1 and G. Splitter 2. Abstract Text References Correspondence and Footnotes. Cellular immune responses are a critical part of the host's defense against intracellular bacterial infections.
Immunity to Brucella abortus crucially depends on antigen-specific T cell-mediated activation of macrophages, which are the major effectors of cell-mediated killing of this organism. T lymphocytes that proliferate in response to B. Human, murine, and bovine T lymphocytes exhibited a type 1 cytokine profile, suggesting an analogous immune response in these different hosts.
In vivo protection afforded by a particular cell type is dependent on the antigen presented and the mechanism of antigen presentation. These transgenic macrophage clones induced partial protection in mice against experimental brucellosis.
Knowing the cells required for protection, vaccines can be designed to activate the protective T cell subset. Lastly, as a new strategy for priming a specific class I-restricted T cell response in vivo , we used genetic immunization by particle bombardment-mediated gene transfer. Key words: T cell subsets, Brucella abortus , knockout mice, cytokines, intracellular pathogens, genetic immunization. Intracellular bacteria are microbial pathogens which share several common features and include a variety of organisms such as Listeria monocytogenes , Salmonella typhimurium , Mycobacterium tuberculosis and Brucella abortus.
Optimal protective immunity to intracellular bacteria usually requires the combination of different elements of the immune system to orchestrate cellular responses leading to protection. To be more precise, resistance to facultative intracellular bacterial pathogens depends on acquired cell-mediated immunity and activation of macrophages by T lymphocytes.
A critical cell-mediated mechanism responsible for protection is gamma-interferon IFN- g up-regulation of macrophage antimicrobial activity. Therefore, effective protective immunity against intracellular infectious agents is contingent on the activation of the appropriate cytokine-producing T lymphocytes. The T cell system can be separated into stable subsets according to their use of T cell receptors, accessory molecules that interact with the MHC gene products on target cells, and cytokine profile.
Recently, optimal protection against intracellular bacteria is regarded as a coordinated interaction between different T cell subsets 2. Brucella abortus is a Gram-negative facultative intracellular bacterium that infects humans and domestic animals. The pathological manifestations of brucellosis are diverse and include arthritis, endocarditis, undulant fever and meningitis in humans, while bovine brucellosis is characterized by spontaneous abortion 5.
Brucella replicates in host mononuclear phagocytes, and survival in phagocytic cells allows the bacterium to escape the extracellular mechanisms of host response such as complement and antibodies. Therefore, T lymphocyte activation upon vaccination with bacterial proteins appears to be a decisive cell-mediated mechanism to provide resistance to B. Pathogenesis induced by intracellular organisms is the product of a complex series of interactions between the pathogen, the infected host cell, and different elements of the immune system.
Thus, research on the interplay between the immune response and persistent microbial pathogens as well as the characterization of the relevant antigens will help us to understand how the immune system functions against different diseases.
Brucella abortus induces a type 1 cytokine profile in murine, bovine, and human T lymphocytes. Cytokines are key molecules that play a major role in determining a protective or a noncurative immune response. The ability of specific antigens to induce preferentially a Th1 or Th2 T-helper subset response is an important aspect for the development of vaccines against intracellular pathogens 7.
These distinct T cell subsets often influence the outcome of infection through the production of specific cytokines. The objective of this section is to compare the cytokine profiles induced by B.
Understanding the influence of cytokines produced by the innate immune system on the acquisition of adequate T cell responses to an infectious agent is critical to define the pathway of Th or Tc T cytotoxic cell development. It is now becoming clear that the divergence into Th1 and Th2 cells is regulated to some extent by the innate immune response at the onset of infection. Recently, investigators have demonstrated that human monocytes expressed mRNA transcripts for IL p40 at 4 h and secreted IL p40 protein at 24 h after in vitro stimulation with B.
We also demonstrated that adherent murine spleen cells showed an elevated IL p40 gene expression level at 12 to 24 h after stimulation with g -irradiated B. This early production of IL during B. A strong correlation between the level of cytokine mRNA transcripts and the cytokine pattern secreted by T lymphocytes has been established. Additionally, B. In concordance with our studies, others have demonstrated that B. The cytokine transcription profile as well as secreted products are closely similar among murine, bovine, and human T cells upon B.
Identical immune responses mounted by these different species against the same pathogen reinforce the use of animal models to study human diseases and the applicability of immunological information to these species.
The paradigm of disease resolution was based on adoptive T cell transfer or in vivo subpopulation depletion using monoclonal antibodies, both with potential pitfalls. To clarify the controversy about the T cell subsets responsible for B. Research into anti-infectious immunity has enormously benefited from the creation of KO mice by homologous recombination which has not only clarified the essential role of distinct immune components, but also unraveled an extraordinary compensatory capacity of the system.
The animals were sacrificed weekly and B. After the first week post-infection, B. Additionally, the number of B. The cytokine transcription profile and the secreted products were assayed to determine which of these important regulatory molecules are involved in orchestrating the cellular immune response in brucellosis. The results indicated that Brucella -primed splenocytes from all three mouse strains exhibited a type 1 cytokine profile IFN- g was secreted by spleen cells from all mouse strains when the cells were cultured with g -irradiated B.
To elucidate the cytokine network involved in murine brucellosis and its possible role in enhancing resistance or susceptibility to B. In contrast, substantial amounts of IL were detected in splenic culture supernatants from all three mouse strains. IL production by Brucella -activated macrophages may be associated with a high concentration of suppressor macrophages found in mouse spleens two to three weeks after infection.
IFN- g plays a central role in acquired resistance of mice against intracellular bacteria. This cytokine is known to up-regulate macrophage microbial killing activity and to induce the development of Th1 cells. Regarding effector function, B. We suggest that a combination of mechanisms underlie the acquisition of protective immunity against this intracellular bacterium. Figure 1 - Analysis of cytokine gene expression in B.
The results are reported as attomoles. A transfected macrophage cell line presents Brucella peptide in the context of MHC class I molecules. MHC class I molecules primarily present endogenous antigens that are synthesized by antigen-presenting cells and processed within the cytosol.
After cytosolic delivery, proteosomes are proposed to cleave antigens into peptides, which are then transported into the lumen of the endoplasmic reticulum ER via a transporter for antigen presentation.
Interestingly, B. We have identified different B. First, we subcloned B. These constructs were then stably transfected into Raw To confirm gene expression, macrophage clones expressing Brucella genes were screened by Northern blot using the respective probes.
Macrophage clones transfected with Brucella genes were then cultured in the presence of enriched murine Brucella -primed T lymphocytes to measure T cell proliferative responses. However, when anti-CD8 or anti-KD d mAb was included, the proliferation was abrogated to background levels. To investigate if these transgenic macrophage clones indeed induce protective immunity in mice, the transfected Raw Surprisingly, Raw Traditionally, classical vaccines have been produced by the use of attenuated or inactivated pathogens and immunogenic protein subunits of microbes.
Tang et al. Direct inoculation of the gene s of a pathogen should mimic attenuated vaccines since synthesis of specific foreign proteins would be achieved in the host and would be the target of immune surveillance. The understanding of the different pathways for antigen presentation led to the consideration of direct transfection of tissue cells in vivo as an alternative means of obtaining appropriate antigen processing, and thus as an alternative to immunization with live virus, for example.
Genetic immunization is a simple and efficient technique to sensitize T cells. It involves the injection into animals of expression plasmid DNA that encodes the antigen of interest. Transient expression of the DNA in an antigen-presenting cell in the skin, muscle, endothelium or vascular smooth muscle allows the priming of immune responses. DNA immunization has been reported to successfully induce MHC class I-restricted cytotoxic T lymphocyte activity against different pathogens in many different animal models In addition, strong and long-lasting humoral and cellular immune responses are also obtained This novel vaccination approach has been shown to confer protection against influenza virus, rabies virus, hepatitis B virus, malaria, leishmaniasis, and tuberculosis, among others There are basically two main DNA delivery methods: direct injection into skeletal muscle using a syringe and a small gauge needle and particle bombardment or biolistic process using a gene gun device.
Gold microparticles 1. The ear and peritoneal regions were the target for gene gun-based DNA immunization in all animals. This novel approach is a potent strategy for priming class I-restricted T cell responses in vivo , and is important for future vaccine development.
Also, it is particularly relevant for intracellular microbial pathogens, none of which can be satisfactorily hindered by conventional vaccination strategies at present. After washing, the plates were incubated with goat anti-mouse IgG peroxidase conjugate for 2 h. The reaction was developed and absorbance was read at nm. Zinkernagel RM Restriction by H-2 gene complex of transfer of cell-mediated immunity to Listeria monocytogenes. Nature , Journal of Immunology , Major histocompatibility complex class I-restricted T cells are required for resistance to Mycobacterium tuberculosis infection.
CD8 T cells can protect against an intracellular bacterium in an interferon gamma-independent fashion.
Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections
Considerable efforts have been made to better understand the immune system of bottlenose dolphins in view of the common environmental challenges they encounter, such as exposure to polychlorinated biphenyls, oil spills, or harmful algal bloom biotoxins. However, little is known about the identity and functionality of the Th1, Th2, and Treg T helper cell subsets in bottlenose dolphins. The present study aimed at validating assays and reagents to identify T helper cell subsets and their functions in a subset of dolphins from Sarasota Bay, Florida, USA, which have been long studied and often used as a reference population. The lack of an increase in the expression of the genes for the Th2 cytokines IL-4 and IL upon stimulation with IL-4 may be due to the requirement for IL-2 for a Th2 polarization as described in mice. However, regression analysis and PCA suggested the potential ability of both the Th1 and Th2 response to be triggered upon acute inflammatory signals.
Differentiation and Function of T Cell Subsets in Infectious Diseases
In response to cytokine signalling and other factors, CD4-positive T lymphocytes differentiate into distinct populations that are characterized by the production of certain cytokines and are controlled by different master transcription factors. The spectrum of such populations, which was initially limited to Th1 and Th2 subsets, is currently broadened to include Th17 and Treg subsets, as well as a number of less studied subtypes, such as Tfh, Th9, and Th Although these subsets appear to be relatively stable, certain plasticity exists that allows for transition between the subsets and formation of hybrid transition forms. This provides the immune system flexibility needed for adequate response to pathogens but, at the same time, can play a role in the pathogenic processes in cases of deregulation. In this review, we will discuss the properties of T lymphocyte subsets and their plasticity, as well as its implications for cancer and autoimmune diseases.
This is a preview of subscription content, access via your institution. Rent this article via DeepDyve. Bailey, D. An aid to finding identify, linkage, and function of histocompatibility and other genes.
This first thematic issue, of the Advances in Immunology series, highlights the remarkable new insights into the mechanisms that govern development and function of T cell lineages. Recent developments in the understanding of the genetic and epigenetic mechanisms that regulate development of the two major T cell lineages will have a fundamental impact on a number of research fields -immunology, cell biology, hematology and stem cell research.
Genetic control of T-Cell subset representation in inbred mice
The role of T cell subsets and cytokines in the regulation of intracellular bacterial infection. Oliveira 1 , J. Harms 2 , E.
Specification of subsets is a process beginning in intrathymic development and continuing within the circulation. It is highly flexible to adapt to differences in nutrient availability and the tissue microenvironment. This ability is dependent on the metabolic status of the cell, with mTOR acting as the rheostat. Autoimmune and antitumor immune responses are regulated by the balance between regulatory T cells and Th 17 cells. When a homeostatic balance of subsets is not maintained, immunopathology can result. Signals contributing to subset specification include the prevailing cytokine environment, cytokine receptor expression profiles, transcription factor expression, and differential chromatin remodeling of loci that regulate production of effector cytokines [ 4 ]. The molecular basis for cytokine memory involves imprinting gene loci encoding cytokines by demethylation of DNA or histone acetylation as cells progress through S phase, so stable patterns of gene expression occur with an increasing number of cell divisions [ 6 ].
PDF | This review is focused on different subsets of T cells: CD4 and CD8, memory and effector functions, and their role in CAR-T therapy--a.
T Lymphocyte Plasticity in Autoimmunity and Cancer
Determining the presence of naive, memory, and activated T cells in various clinical contexts including autoimmune diseases, immunodeficiency states, T-cell recovery post-hematopoietic stem cell transplant, DiGeorge syndrome, and as a measure for T-cell immune competence. Evaluation of T-cell reconstitution after hematopoietic stem cell transplant, chemotherapy, biological therapy, immunosuppression, or immunomodulator therapy. Evaluation of T-cell immune competence presence of memory and activated T cells in patients with recurrent infections. T cells, after completing development and initial differentiation in the thymus, enter the periphery as naive n T cells. Naive T cells undergo further differentiation into effector and memory T cells in the peripheral lymphoid organs after recognizing specific antigenic peptides in the context of major histocompatibility MHC molecules, through the antigen-specific T-cell receptor. In addition to the cognate signal of the peptide-MHC complex interaction the term cognate refers to 2 biological molecules that normally interact , T cells require additional costimulatory signals to complete T-cell activation. Naive T cells circulate continuously through the lymph nodes and, on recognition of specific antigen, undergo activation.
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