pediagenosis: Immunology
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Showing posts with label Immunology. Show all posts
Showing posts with label Immunology. Show all posts

Friday, November 6, 2020

B‐CELLS RESPOND TO THREE DIFFERENT TYPES OF ANTIGEN

B‐CELLS RESPOND TO THREE DIFFERENT TYPES OF ANTIGEN

B‐CELLS RESPOND TO THREE DIFFERENT TYPES OF ANTIGEN

There are three main types of Bcell that respond to infection by secreting antibodies that target specific classes of microbes, with the particular function of each Bcell subset generally determined by their location. Follicular Bcells (also called B2 cells) express highly specific monoreactive Bcell receptors (BCRs), are present in the lymphoid follicles of the spleen and lymph nodes, and typically require Tcells in order to generate highaffinity antibodies, and to undergo class switching (Figure 7.21). However, as we shall discuss below, certain types of antigens (called Tindependent antigens) can promote Bcell activation without the help of Tcells. The antibodies thus formed are typically of low affinity and do not undergo class switching or somatic hypermutation but provide rapid protection from certain microorganisms and buy time for Tdependent Bcell responses to be made. Such rapid antibody responses are mediated by the “innate like” Bcells; B1 and marginal zone (MZ) Bcells, which express polyreactive BCRs that are of broad specificity and enable them to recognize multiple different kinds of evolutionarily conserved microbial antigens. In this way, they are similar to the Tolllike receptors (TLRs) expressed on conventional innate immune cells. Indeed, innatelike Bcells also express TLRs and can be directly acti­vated by PAMPs, act as APCs, and secrete cytokines, which places them at the interface between the innate and adaptive immune systems. Importantly, this innatelike Bcell response is positioned at strategic areas that are sensitive to microbial invasion, such as the skin, mucosa, and the marginal zone of the spleen, where the lymphatic and circulatory systems converge.

DYNAMIC INTERACTIONS AT THE IMMUNOLOGICAL SYNAPSE

DYNAMIC INTERACTIONS AT THE IMMUNOLOGICAL SYNAPSE

DYNAMIC INTERACTIONS AT THE IMMUNOLOGICAL SYNAPSE

As we have described above, successful TCR triggering involves a multitude of signal transduction events that culminate in Tcell activation. But what is the probability of this occurring in an in vivo setting? Tcells need to be highly efficient at finding their cognate antigen and discriminating between activating and non-activating peptideMHC complexes for several reasons.

DAMPING T‐CELL ENTHUSIASM

DAMPING T‐CELL ENTHUSIASM

DAMPING T‐CELL ENTHUSIASM

We have frequently reiterated the premise that no selfrespecting organism would permit the operation of an expanding enterprise such as a proliferating Tcell population without some sensible controlling mechanisms. There are some similarities here with regulations governing corporate takeovers in the business world, where it has been deemed prudent to ensure that no single enterprise is permitted to completely dominate the marketplace. Such monopoly practices, if allowed to occur in an unregulated way, would eventually eliminate all competition. Not a good thing for diversity or overall fitness.

Thursday, November 5, 2020

METABOLIC CONTROL OF T‐CELL DIFFERENTIATION

METABOLIC CONTROL OF T‐CELL DIFFERENTIATION

METABOLIC CONTROL OF T‐CELL DIFFERENTIATION

It should now be clear that metabolic reprogramming plays a crucial role in Tcell activation. However, the regulation does not end there. Specific metabolic programs are not only essential for the immunestimulatory function of particular Tcell subsets, the individual nature of the metabolic signal also plays a crucial role in determining differentiation to the extent that inhibiting one metabolic signal over another is sufficient to shunt Tcell differentiation towards a different outcome. Genetic studies have revealed an essential role for the mTOR pathway in promoting Th1, Th2, and Th17 differentiation, with stimulation of mTORdeficient cells leading mainly to differentiation of Tregs, which outlines a crucial role for mTOR in promoting effector Tcell (Teff ) differentiation (Figure 7.17). Indeed, the layers of mTOR regulation extend to individual effector Th populations, with deletion of the mTORC1 activator Rheb biasing toward the Th2 effector cell phenotype while deletion of RICTOR, an essential component of the mTORC2 complex, favors generation of mainly Th1 and Th17 effectors (Figure 7.17). Thus, mTORC1 activation directs differentiation towards Th1 and Th17, while mTORC2 promotes Th2 production. While mTOR activation can skew towards Th1 or Th2 phenotypes, HIF1α has a particularly important role in the differentiation of Th17 cells by activating the Th17specific master transcription factor RORγt. In addition, HIF1α can also bind the Tregspecific master regulator Foxp3, promoting its degradation and the inhibition of Treg differentiation. As such, genetic deletion of HIF1α blocks Th17 responses and skews differentiation to Treg cells.

ACTIVATED T‐CELLS UNDERGO AN ESSENTIAL METABOLIC SHIFT

Metabolic reprogramming drives Tcell activation and effector differentiation

It should now be apparent that lymphocyte activation triggers a myriad of signaling pathways that radically transform resting Tcells in preparation for effector function, and recent developments have uncovered a crucial role for specific metabolic pathways in not only fueling these changes, but in directing the outcome of Tcell differentiation into specific effector subtypes. Activated Tcells not only differ metabolically from their quiescent counterparts, differentiation into the various effector populations cannot proceed without distinct metabolic reprogramming.

EPIGENETIC CONTROL OF T‐CELL ACTIVATION

EPIGENETIC CONTROL OF T‐CELL ACTIVATION

EPIGENETIC CONTROL OF T‐CELL ACTIVATION

Epigenetic control of gene expression regulates Tcell activation and differentiation

Activation and differentiation of Tcells into the correct effector subsets is fundamental to generating an immune response capable of fighting a specific infection. Accordingly, the genes controlling Tcell activation and differentiation are tightly controlled. Nuclear DNA is normally wrapped around proteins called histones, which act as spools around which DNA winds, allowing the cell to compact and order a large amount of genetic information into the relatively small confines of the nucleus. Importantly, histones act as guardians of genetic information by shielding genes from activating transcription factors and as such, histone modification introduces a important layer of regulation of gene expression. For example, posttranslational modifications of histones at specific amino acids may directly change the conformation of histone at that site and effectively loosen or tighten its grip on DNA, thereby making it more or less accessible for transcription factor binding and gene activation. This can also occur indirectly, where histone modification creates a binding site for chromatinmodifying factors, which can then change the structure of chromatin to activate or repress gene transcription at a particular locus. ChIPsequencing (ChipSeq) is an experimental technique that combines chromatin immunoprecipitation with largescale DNA sequencing to detect binding sites between proteins and DNA on a genomewide scale. This technology has uncovered many important histone modifications, including trimethylation of histone H3 at lysine 4 (H3K4me3), which promotes an active chromatin arrangement at particular genes, and H3K27me3, which may tighten chromatin and repress gene transcription. In addition, direct methylation of DNA at CpG sites may render genes less transcriptiona ly active and this can play an important role in gene regulation.

ACTIVATED T‐CELLS EXHIBIT DISTINCT GENE EXPRESSION SIGNATURES

ACTIVATED T‐CELLS EXHIBIT DISTINCT GENE EXPRESSION SIGNATURES

ACTIVATED T‐CELLS EXHIBIT DISTINCT GENE EXPRESSION SIGNATURES

Because there are a multitude of infectious agents, running the gamut from viruses, intracellular bacteria, large parasitic worms, extracellular bacteria, yeast, and other fungi, the reader will not be too surprised to learn that activated Tcells become specialized towards dealing with the particular class of infectious agent that caused them to be woken from their slumber. This process, called Tcell polarization, will be dealt with more fully in Chapter 8, but we will introduce it here because it is inextricably linked to Tcell activation. Because of the diversity of intraand extracellular pathogens, activated Tcells must differentiate into distinct types of effector Tcells, specifically tailored to tackle a particular class of invader. As we have mentioned in previous chapters, activated Tcells can undergo differentiation into at least three distinct subclasses: Thelper (Th) cells, cytotoxic Tcells (CTLs), and regulatory Tcells (Treg). CD4+ Tcells coordinate immune responsesby differentiating into distinct Thelper subsets that tailor the immune response towards the particular infectious agent. Thelper cells achieve this by releasing powerful inflammatory cytokines, which direct the subsequent responses of CD8+ Tcells, Blymphocytes, and cells of the innate immune system such as macrophages. Recent studies have suggested that during the clonal expansion phase, the differentiation process starts as early as the second cell doubling, and in this context, activation and differentiation can be viewed as two halves of the same coin. Cumulatively, Tcell activation and differentiation promotes the upregulation of a myriad of genes and we will now consider the most important of these (Figure 7.13).

CD28 CO‐STIMULATION AMPLIFIES TCR SIGNALS AND BLOCKS APOPTOSIS

CD28 CO‐STIMULATION AMPLIFIES TCR SIGNALS AND BLOCKS APOPTOSIS

CD28 CO‐STIMULATION AMPLIFIES TCR SIGNALS AND BLOCKS APOPTOSIS

As we have frequently noted, naive Tcells typically require two signals for proper activation: one derived from TCR ligation (signal 1) and the other provided by simultaneous engagement of CD28 on the Tcell (signal 2) by CD80 (B7.1) or CD86 (B7.2) on the DC (Figure 7.3). Indeed, Tcells derived from CD28deficient mice, or cells treated with antiCD28 blocking antibodies, display severely reduced capacity to proliferate in response to TCR stimulation in vitro and in vivo. Moreover, CD28 deficiency also impairs Tcell differentiation and the production of cytokines required for Bcell help. Similar effects are also seen when CD80 or CD86 expression is interfered with. So what does tickling the CD28 receptor do that is so special?

Wednesday, October 21, 2020

T‐LYMPHOCYTES AND ANTIGEN‐PRESENTING CELLS INTERACT THROUGH SEVERAL PAIRS OF ACCESSORY MOLECULES

T‐LYMPHOCYTES AND ANTIGEN‐PRESENTING CELLS INTERACT THROUGH SEVERAL PAIRS OF ACCESSORY MOLECULES

T‐LYMPHOCYTES AND ANTIGEN‐PRESENTING CELLS INTERACT THROUGH SEVERAL PAIRS OF ACCESSORY MOLECULES

Before we delve into the nuts and bolts of TCRdriven signaling events, it is important to recall that Tcells can only recognize antigen when presented within the peptidebinding groove of major histocompatibility complex (MHC) molecules. Furthermore, while the TCR is the primary means by which Tcells interact with the MHCpeptide complex, Tcells also express coreceptors for MHC (either CD4 or CD8) that define functional Tcell subsets. Recall that CD4 molecules act as coreceptors for MHC class II and are found on Thelper cell populations that provide “help” for activation and maturation of Bcells and cytotoxic Tcells (Figure 7.1). CD8 molecules act as coreceptors for MHC class I molecules and are a feature of cytotoxic Tcells that can kill virally infected or precancerous cells (Figure 7.1). Note, however, that the affinity of an individual TCR for its specific MHC–antigen peptide complex is relatively low (Figure 7.2). Thus, a sufficiently stable association with an antigenpresenting cell (APC) can only be achieved by the interaction of several complementary pairs of accessory molecules such as LFA1/ICAM1, CD2/LFA3, and so on (Figure 7.3). These adhesion molecules enable Tcells to associate with DCs and other APCs for the purposes of inspecting the peptides being presented within MHC molecules (Figure 7.4). However, these molecular couplings are not necessarily concerned with intercellular adhesion alone; some of these interactions also provide the necessary costimulation that is essential for proper lymphocyte activation.

THE ACTIVATION OF T‐CELLS REQUIRES TWO SIGNALS

THE ACTIVATION OF T‐CELLS REQUIRES TWO SIGNALS

THE ACTIVATION OF T‐CELLS REQUIRES TWO SIGNALS

Stimulation of the TCR by MHC–peptide (which can be mimicked by antibodies directed against the TCR or CD3 complex) is not sufficient to fully activate resting helper Tcells on their own. Upon costimulation via the CD28 receptor on the Tcell, however, RNA and protein synthesis is induced, the cell enlarges to a blastlike appearance, interleukin2 (IL2) synthesis begins and the cell moves from G0 into the G1 phase of the cell division cycle. Thus, two signals are required for the activation of a naive helper Tcell (Figure 7.3).

TRIGGERING THE T‐CELL RECEPTOR COMPLEX

TRIGGERING THE T‐CELL RECEPTOR COMPLEX

TRIGGERING THE T‐CELL RECEPTOR COMPLEX

Let us now consider a situation in which a Tcell has encountered a DC displaying the correct peptide–MHC combination and has engaged with the DC such that many of the TCRs on the Tcell are engaged with a similar number of highaffinity peptide–MHC molecules on the APC. Such an event will greatly stabilize the interaction between the Tcell and the DC such that the duration of the encounter (the dwell time) will be sufficient to activate the Tcell (Figure 7.4). But what is the actual activating event? Put another way, how does the TCR complex register that the switch has been thrown?

PROTEIN TYROSINE PHOSPHORYLATION IS AN EARLY EVENT IN T‐CELL SIGNALING

PROTEIN TYROSINE PHOSPHORYLATION IS AN EARLY EVENT IN T‐CELL SIGNALING

PROTEIN TYROSINE PHOSPHORYLATION IS AN EARLY EVENT IN T‐CELL SIGNALING

Interaction between the TCR and MHC–peptide complex is greatly enhanced by recruitment of either coreceptor for MHC (CD4 or CD8) into the complex. Furthermore, because the cytoplasmic tails of CD4 and CD8 are constitutively associated with Lck, a protein tyrosine kinase (PTK) that can phosphorylate the three tandemly arranged ITAMs within the TCR ζ chains, recruitment of CD4 or CD8 to the complex results in stable association between Lck and its ζchain substrate (Figure 7.8a).

DOWNSTREAM EVENTS FOLLOWING TCR SIGNALING

DOWNSTREAM EVENTS FOLLOWING TCR SIGNALING

DOWNSTREAM EVENTS FOLLOWING TCR SIGNALING

The Ras–MAP kinase pathway

Ras is a small Gprotein that is constitutively associated with the plasma membrane and is frequently activated in response to diverse stimuli that promote cell division (Figure 7.10). It can exist in two states: GTPbound (active) and GDPbound (inactive). Thus, exchange of GDP for GTP stimulates Ras activation and enables this protein to recruit one of its down­stream effectors, Raf. So how does TCR stimulation result in activation of Ras? One of the ways in which Ras activation can be achieved is through the activity of GEFs (guaninenucleotide exchange factors) that promote exchange of GDP for GTP on Ras. One such GEF, SOS (son of sevenless), is recruited to phosphorylated LAT via the phosphotyrosinebinding protein GRB2 (Figure 7.8). Thus, phosphorylation of LAT by ZAP70 leads directly to the recruitment of the GRB2/SOS complex to the plasma membrane where it can stimulate activation of Ras through promoting exchange of GDP for GTP.

Thursday, September 24, 2020

THE HANDLING OF ANTIGEN

THE HANDLING OF ANTIGEN

THE HANDLING OF ANTIGEN

Where does antigen go when it enters the body? If it penetrates the tissues, it will be carried by the lymph to the draining lymph nodes. Antigens that are encountered in the upper respiratory tract, intestine, or reproductive tract are dealt with by the local MALT, whereas antigens in the blood provoke a reaction in the spleen.

BONE MARROW IS A MAJOR SITE OF ANTIBODY SYNTHESIS

BONE MARROW IS A MAJOR SITE OF ANTIBODY SYNTHESIS

BONE MARROW IS A MAJOR SITE OF ANTIBODY SYNTHESIS

Although B‐cells mature in the bone marrow from hematopoietic stem cells, upon maturation most naive B‐cells leave for the secondary lymphoid tissues where they can encounter antigen. This release from the bone marrow may be regulated by sphingosine 1‐phosphate, which is known to control the exit of lymphocytes from the thymus and lymph nodes. 

SPLEEN

SPLEEN

SPLEEN

The spleen is divided into the white pulp, which includes the periarteriolar lymphoid sheaths (PALS) and functions as a secondary lymphoid tissue, and the macrophagerich red pulp, which is responsible for the removal by phagocytosis of aging erythrocytes, platelets, and some bloodborne pathogens. 

LYMPH NODES

LYMPH NODES

LYMPH NODES

The encapsulated tissue of the lymph nodes acts as a filter for lymph draining the body tissues (Figure 6.15a). The lymph, which will contain any foreign antigens present in the tissues, enters the subcapsular sinus (space) via the afferent lymphatic vessels. The subcapsular sinus constitutes a continuous area beneath the capsule that surrounds the entire lymph node and, together with the trabecular sinuses which pass through the body of the lymph node, allow larger antigens to either be engulfed by the resident macrophages lining the subcapsular and medullary sinuses, or to pass unimpeded to the efferent lymphatics (Figure 6.12 and Figure 6.15b). The resident macrophages, together with dendritic cells that have taken up antigen in the tissues and arrive via the afferent lymphatics, can both act as APCs for T‐cells in the lymph node.

Wednesday, September 23, 2020

LYMPHOCYTE HOMING

LYMPHOCYTE HOMING

LYMPHOCYTE HOMING

This traffic of lymphocytes throughout the body enables these antigen‐specific cells to seek “their” antigen and to be deployed to sites at which a response is required. When antigen reaches a lymph node in a primed animal, there is a dramatic fall in the output of cells in the efferent lymphatics, a phenomenon described variously as “cell shutdown” or “lymphocyte trapping.” This process involves a reduced responsiveness of lymphocytes to sphingosine 1‐phosphate (S1P), a molecule that signals lymphocytes to exit the lymph node. The shutdown phase is followed by an output of activated cells that peaks at around 80 hours.

Organized Lymphoid Tissue

Organized Lymphoid Tissue

Organized Lymphoid Tissue

The role of the bone marrow in hematopoiesis and of the thymus in T‐cell development will be discussed in Chapter 10. As already discussed, the MALT deals with antigens present at mucosal surfaces. In contrast, the lymph nodes receive antigen either draining directly from the tissues or carried by dendritic cells, and the spleen monitors the blood. 

Wednesday, August 26, 2020

The Blood and Lymphatic Systems

The Blood and Lymphatic Systems


The Blood and Lymphatic Systems
As mentioned already, many cells of the immune system, particularly lymphocytes, NK cells, monocytes, neutrophils, eosinophils, and basophils travel around the body in the blood and lymph. Both the blood vessels and lymphatic vessels are lined with a type of epithelial cell referred to as endothelium. As infectious agents can, collectively, infect any organ or tissue, this motility of the immune system is essential in order to protect the whole body. Leukocytes are carried through the blood circulation by the pumping action of the heart, and travel from the heart through the arteries to eventually reach the capillaries found throughout the tissues. The leukocytes can continue their journey in the veins, which contain internal valves to ensure the blood continues to flow in the correct direction, eventually leading back to the heart. Thus leukocytes can go around the body again and again via the blood circulation. The system of lymphatic vessels (Figure 6.10) is also distributed throughout the body and makes physical connections with the blood circulation in the thorax (the chest). Here a lymphatic vessel called the thoracic duct (also referred to as the left lymphatic duct) joins up with the left subclavian vein, while the right lymphatic duct joins to the right subclavian vein.

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