Guide Immune Reactivity of Lymphocytes: Development, Expression, and Control

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However, the establishment of this adaptive immune response is often not fast enough to eradicate pathogens, and it also involves cell proliferation, genetic activation, and protein synthesis [ ]. Thus, the fastest defense of a host mechanism is provided by the innate immune system, which has developed the ability to recognize invading pathogens and thus effectively eliminate them so that they do not cause damage to host cells.

The recognition of pathogens occurs through cells involved in the innate immunity response by nonspecific molecules that are commonly shared by most pathogens called PAMPs. PAMPs are highly conserved products and are produced by numerous microorganisms. These PAMPs do not show specific structures with antigenic variability, and host cells do not share the same molecular patterns with pathogens, resulting in recognition of the immune system, capable to discriminate between self and nonself [ ]. However, pathogens are not the only cause of cell and tissue damage. DAMPs include any endogenous molecule that experiences a change of state in association with a tissue injury, which allows the immune system to be informed that any damage has occurred [ ].

Regulatory T Cells (Tregs)

When these DAMPs are released from damaged or necrotic cells, together with PAMPs, are recognized by certain PRRs for their subsequent activation and induction of a potent acute inflammatory response [ ]. They were originally identified in the Drosophila fly as an important gene for its ontogenesis and its immunological resistance against fungal infections.

In addition, it was found that during microbial infections of flies, Toll receptors induce the production of antimicrobial peptides [ ]. In humans, the first protein structurally related to the Drosophila Toll receptor was identified and called the Toll-1 receptor TLR TLR-3 recognizes double-stranded RNA ligands, which are produced by most viruses in replication stages.

TLR-5 responds to bacterial flagellin ligands. TLR-9 binds to ligands containing CpG motifs [ ]. TLRs are a family of transmembrane receptors that are key in the response and regulation of both innate and adaptive immunity [ ], since they recognize diverse pathogens and help to eliminate them. There are other receptors such as NLRs, which are a family of 23 members that have been identified in humans. Among the most important members of these receptors are NOD1 and NOD2, which recognize specific ligands from various pathogens.

Regulation of antitumour CD8 T-cell immunity and checkpoint blockade immunotherapy by Neuropilin-1

This family is involved in increasing the proinflammatory events caused by cell death, pyroptosis and pyronecrosis, and several more proinflammatory processes [ ]. Another family of receptors is the RIGs. They are intracellular recognition receptors for patterns involved in the recognition of viruses by the action of the innate immune system. They act as sensors for viral replication within human host cells necessary to mediate antiviral responses [ ]. In innate immunity, a large number of soluble mediators such as cytokines, chemokines, and the complement system participate.

All these mediators provide protection in the initial phase of contact with pathogens and are responsible for preventing potentially harmful infections. The complement system has been considered as an effector response of the innate immune system capable of eliminating a great diversity of pathogens including bacteria, viruses, and parasites [ ]. The complement system is composed of plasma proteins, which are present as inactive proteins [ ].

After activation, the products that are generated from the complement system facilitate the recruitment of cells from the immune system to the site of damage to eliminate the pathogen through opsonization or direct destruction [ ]. Activation of the complement system occurs through three pathways: 1 the classical pathway for the antigen—antibody complex; 2 the alternating pathway through the spontaneous hydrolysis of C3; and 3 the lectin pathway where certain sugars are recognized on the surface of the pathogens through mannose-binding lectin MLB.

Once activated, the pathway of the complement system generates a multimolecular enzyme complex that cuts to C3 and forms C3a and C3b. The C3b fragment that is generated binds to C3 convertase to form the C5 convertase, and once formed, this complex cuts to C5 to form C5a and C5b [ ]. Then, C5b begins to recruit complement components C6, C7, C8, and C9 to form the membrane attack complex which is a lytic pore inserted into the membrane of the pathogen [ ].

Since the complement system uses multiple activation pathways, it has the ability to maximize the number of pathogens that it can recognize and thus eliminating a great diversity of these. In addition, it is responsible for eliminating apoptotic cells, this occurs through depositing a low amount of C3b molecules which facilitates the removal of these cells by macrophages [ ].

Cytokines form a molecular network that is synthesized and released by different cell types. These molecules act in a paracrine and endocrine way through their receptors that express the target cell. These molecules are synthesized and released in response to some damage or recognition of specific structures of the pathogens through their receptors e.

Initially, the cytokines were defined based on the activity they performed, among these activities are regulating the immune system but also exerting an effector function on the cells, these effects not only occur at local level but also occur through the tissues or systems. Cytokines are involved in regulating the homeostasis of the organism but when its production or its signaling pathway in the cell is not regulated, this homeostasis is altered, which can trigger in a pathology [ , ].

Cytokines may increase systemic level during some pathological condition, either acute or chronic, these molecules exert their effect by binding to their receptors, where the signal translation is given, which leads to the gene expression and finally can regulate the function of the target cell. The cytokine pattern that is released from the cell depends primarily on the nature of the antigenic stimulus and the type of cell being stimulated.

Cytokines compromise leukocytes to respond to a microbial stimulus, through regulating positively the expression of adhesion molecules on endothelial cells and amplifying the release of molecules such as reactive oxygen species and nitrogen, histamine, serotonin, as well as arachidonic acid derivatives, which regulate the release of the cytokines. On the other hand, cytokines can promote apoptosis by binding to receptors that contain death domains, for example TNF receptor 1 R1 [ ].

Chemokines or chemotactic cytokines are small molecules which constitute a large family of peptides 60— amino acids structurally related to cytokines.

Their main function is to stimulate leukocyte migration. They are secreted in response to some signals such as proinflammatory cytokines, where they play an important role in selectively recruiting monocytes, neutrophils, and lymphocytes [ , ]. The CC chemokine family is the largest and can be subdivided into several subfamilies. The second family consists of CXC chemokines; the prototype of these chemokines is IL-8 CXCL8 ; mainly this chemokine attracts polymorphonuclear cells to the site of acute inflammation.

Also, CXCL8 activates monocytes and can recruit these cells to vascular injury. The third family, consisting of a single member is Fraktalkine CX3CL1 which is one of the two transmembrane chemokines and has two isoforms, one binds to the membrane and the other is a soluble form. According to its isoform, it may have different functions, the form that is anchored to the membrane serves as adhesion molecule for cells expressing CX3CR1, while the soluble form possesses a potent chemotactic activity [ ].

The fourth family has only one member lymphotoxin XCL1 ; this chemokine is similar to members of the CC and CXC families, but the lack of two of the four cysteine residues are characteristic of this chemokine.

Introduction

Its chemotactic function is for lymphocytes and not for monocytes and neutrophils as do other chemotactic chemokines [ ]. Inflammation is a protective response to extreme challenges to homeostasis, such as infection, tissue stress, and injury [ ], which is characterized by its cardinal signs: redness, swelling, heat, pain, and disrupted function [ ]. A typical inflammatory response consists of four components: 1 inflammatory inducers: depending on the type of infection bacterial, viral, fungi or parasitic [ ]; 2 sensors that detect the inflammatory inducers: these sensors are receptors of the innate immune system such as TLRs, NLRs and RLRs [ , ]; 3 inflammatory mediators induced by the sensors, such as cytokines, chemokines and the complement system [ ]; 4 target tissues that are affected by the inflammatory mediator.

Each component comes in multiple forms and their combinations function in distinct inflammatory pathways. The inflammatory reaction is characterized by successive phases: 1 silent phase, where cells reside in the damaged tissue releases in the first inflammatory mediators, 2 a vascular phase, where vasodilation and increased vascular permeability occur, 3 cellular phase, which is characterized by the infiltration of leukocytes to the site of injury [ ], and 4 resolution of inflammation, which is the process to return tissues to homeostasis [ , ].

In an infection by extracellular bacteria, the host triggers a series of responses to combat the pathogen and prevent its spread. Both the alternative and the lectin pathways of the complement system participate in the bacteria opsonization and potentiate their phagocytosis. To perform the correct phagocytosis, activation of several surface receptors in phagocytes, including scavenger receptors, mannose, Fc, and mainly TLRs is required.

Activation of these receptors results in inflammation, by recruiting leukocytes to the site of infection [ ]. On the other hand, the humoral adaptive immune response is the main protective against extracellular bacteria. Its primary function is to block infection, through the release of antibodies that are directed against the antigens of the bacterial cell wall, as well as of the toxins secreted by certain extracellular bacteria. The effector mechanisms used by the antibodies include neutralization, opsonization, and classical complement pathway activation, which allow bacteria phagocytosis.

The Th17 cells are also involved in recruiting monocytes and neutrophils, promoting local inflammation. Immune response against bacteria. Mechanisms of the innate immune response to eradicate bacteria are A phagocytosis, B inflammatory response, and C participation of the complement system. Description in the text. In the case of infection by intracellular bacteria, they have the ability to survive and replicate within phagocytic cells, which causes the circulating antibodies to be inaccessible to intracellular bacteria.

The innate immune response against these bacteria is mediated primarily by phagocytes and NK cells [ ]. Among the phagocytes involved are neutrophils and then macrophages. However, these pathogens are resistant to degradation, but their products are recognized by TLRs and NLR receptors that are responsible for activating more phagocytes. NK cells are also activated in this type of infections and participate by stimulating the production of cytokine IL by DCs and macrophages.

But usually this immune response is ineffective against infection. All this to eradicate the infection of the host [ ]. Most fungi are present in the environment, so animals including humans are exposed and then can inhale spores or yeasts [ ]. The mechanisms for defense against the fungi comprise of both innate and adaptive immune responses. TLR2 activation induces oxidative pathways in polymorphonuclear PMN cells with the release of gelatinases and inflammatory cytokines.

TLRs can be combined to recognize a large number of fungal structures and thus generate a broader response against the various fungal structures [ , ]. Type C lectin receptors CTLRs make up a receptors family that can recognize several molecules like proteins, carbohydrates, and lipids.

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Among these receptors, the best studied are dectin-1, dectin-2, dendritic cell-specific intercellular adhesion moleculegrabbing nonintegrin DC-SIGN , macrophage inducible C-type lectin, and mannose receptor MR involved in the recognition of some structures of the fungi [ ]. Dectin-1 activation can also induce mast cells to produce proinflammatory and TH2-polarizing cytokines, such as IL-4 and IL In addition, dectin-2 promotes Th17 polarization by inducing ILA, which is crucial in neutralizing some fungi.

The MR recognizes mannose, fucose, or N-acetylglucosamine residues present in fungi. MR generates a Th17 response and promotes fungi phagocytosis [ ]. The response that occurs through the activation of these receptors includes the binding to fungi and their phagocytosis, the induction of antifungal effector mechanisms and the production of soluble mediators such as cytokines, chemokines, and inflammatory lipids [ ].

Frontiers | Tissue-Resident Lymphocytes Across Innate and Adaptive Lineages | Immunology

The immunity against fungi requires the recruitment and activation of phagocytosis, which is mediated through factors that induce inflammatory molecules such as proinflammatory cytokines and chemokines. The PRRs interaction with fungal structures plays an important role in the control of infections against these pathogens, since this interaction is determinant for the generation of the profile of cytokines or chemokines that influence the immune response. Finally, cytotoxic T cells are the primary effector cells for cellular immunity. They recognize and target cells that have been infected by intracellular pathogens , destroying infected cells along with the pathogens inside.

For both helper T cells and cytotoxic T cells, activation is a complex process that requires the interactions of multiple molecules and exposure to cytokines. The T-cell receptor TCR is involved in the first step of pathogen epitope recognition during the activation process. The TCR comes from the same receptor family as the antibodies IgD and IgM, the antigen receptors on the B cell membrane surface, and thus shares common structural elements. A T-cell receptor spans the cytoplasmic membrane and projects variable binding regions into the extracellular space to bind processed antigens associated with MHC I or MHC II molecules.

TCRs are epitope-specific, and it has been estimated that 25 million T cells with unique epitope-binding TCRs are required to protect an individual against a wide range of microbial pathogens. Because the human genome only contains about 25, genes, we know that each specific TCR cannot be encoded by its own set of genes.

This raises the question of how such a vast population of T cells with millions of specific TCRs can be achieved. The answer is a process called genetic rearrangement , which occurs in the thymus during the first step of thymic selection. The genes that code for the variable regions of the TCR are divided into distinct gene segments called variable V , diversity D , and joining J segments.

All the possible combinations of rearrangements between different segments of V, D, and J provide the genetic diversity required to produce millions of TCRs with unique epitope-specific variable regions. Activated helper T cells can differentiate into one of four distinct subtypes, summarized in Table 2. The differentiation process is directed by APC-secreted cytokines. The two types of helper T cells are relatively short-lived effector cells , meaning that they perform various functions of the immediate immune response. T H 1 cells secrete their own cytokines that are involved in stimulating and orchestrating other cells involved in adaptive and innate immunity.

For example, they stimulate cytotoxic T cells, enhancing their killing of infected cells and promoting differentiation into memory cytotoxic T cells. T H 1 cells also stimulate macrophages and neutrophils to become more effective in their killing of intracellular bacteria. They can also stimulate NK cells to become more effective at killing target cells.

T H 2 cells play an important role in orchestrating the humoral immune response through their secretion of cytokines that activate B cells and direct B cell differentiation and antibody production.

Various cytokines produced by T H 2 cells orchestrate antibody class switching , which allows B cells to switch between the production of IgM, IgG, IgA, and IgE as needed to carry out specific antibody functions and to provide pathogen-specific humoral immune responses. A third subtype of helper T cells called T H 17 cells was discovered through observations that immunity to some infections is not associated with T H 1 or T H 2 cells.

Patients who lack sufficient T H 17 cells in the mucosa e. After the successful co-recognition of foreign epitope and self-antigen, the production of cytokines by the APC and the cytotoxic T cell activate clonal proliferation and differentiation. Activated cytotoxic T cells can differentiate into effector cytotoxic T cells that target pathogens for destruction or memory cells that are ready to respond to subsequent exposures.

As noted, proliferation and differentiation of cytotoxic T cells is also stimulated by cytokines secreted from T H 1 cells activated by the same foreign epitope. The co-stimulation that comes from these T H 1 cells is provided by secreted cytokines. Although it is possible for activation of cytotoxic T cells to occur without stimulation from T H 1 cells, the activation is not as effective or long-lasting. Once activated, cytotoxic T cells serve as the effector cells of cellular immunity, recognizing and kill cells infected with intracellular pathogens through a mechanism very similar to that of NK cells.

However, whereas NK cells recognize nonspecific signals of cell stress or abnormality, cytotoxic T cells recognize infected cells through antigen presentation of pathogen-specific epitopes associated with MHC I. Perforin is a protein that creates pores in the target cell, and granzymes are proteases that enter the pores and induce apoptosis. This mechanism of programmed cell death is a controlled and efficient means of destroying and removing infected cells without releasing the pathogens inside to infect neighboring cells, as might occur if the infected cells were simply lysed.

Once activated, the CTL releases perforin and granzymes that invade the infected cell and induce controlled cell death, or apoptosis. When T cell activation is controlled and regulated, the result is a protective response that is effective in combating infections. However, if T cell activation is unregulated and excessive, the result can be a life-threatening. Certain bacterial and viral pathogens produce toxins known as superantigens see Virulence Factors of Bacterial and Viral Pathogens that can trigger such an unregulated response.

Known bacterial superantigens include toxic shock syndrome toxin TSST , staphylococcal enterotoxins , streptococcal pyrogenic toxins , streptococcal superantigen , and the streptococcal mitogenic exotoxin. Viruses known to produce superantigens include Epstein-Barr virus human herpesvirus 4 , cytomegalovirus human herpesvirus 5 , and others. The result is an excessive, uncontrolled release of cytokines, often called a cytokine storm , which stimulates an excessive inflammatory response. This can lead to a dangerous decrease in blood pressure, shock, multi-organ failure, and potentially, death.

Because the T cell does not recognize the epitope, it is not activated. This nonspecific, uncontrolled activation of the T cell results in an excessive release of cytokines that activate other T cells and cause excessive inflammation. Melissa, an otherwise healthy year-old woman, is brought to the emergency room by her concerned boyfriend.

She complains of a sudden onset of high fever, vomiting, diarrhea, and muscle aches. In her initial interview, she tells the attending physician that she is on hormonal birth control and also is two days into the menstruation portion of her cycle. She is on no other medications and is not abusing any drugs or alcohol. She is not a smoker. She is not diabetic and does not currently have an infection of any kind to her knowledge.

The physician believes she is likely suffering from toxic shock syndrome TSS. Inflammation and autoinflammation 9. T cell mediated autoimmune diseases Antibody-mediated autoimmune diseases Special Focus Area 1. Primary Immunodeficiencies 2. Immunity to TB 4. Immunity to Malaria 5. Immunity to HIV 6. Thymic T Cell Development 7. Systems Vaccinology 2. Vaccine Development 3. Adjuvants 4. DNA Vaccines 5. Mucosal Vaccines 6. Infant Immunity and Vaccines 2. Dendritic Cells 3. Conventional T Cells 4. Immunity to Viral Infections 6. Immunity to Helminth Infections 7.

Immunity to TB 8. Immunity to Malaria 9. Introduction to Immunization Strategies 2. Immune Responses to Vaccination 3. Models for Testing Vaccines 4. Immune Escape 5. Neutrophils 2. Exosomes 4. Immunity to Leishmania 6. Immunity to HIV 7. Immunity to Helminth Infections 8. Immunity to TB 9. Cancer Epidemiology and Etiology 2.

T lymphocyte mediated immunity 3.