Antigen Presentation

For example, antigen presentation by CD1a, CD1b, and CD1c initiate a cellular inflammatory response that culminates in granulomatous lung disease.

From: Immunology for Pharmacy , 2012

The Virus as a Concept – Fundamentals of Virology

Andrew J. McMichael , in Encyclopedia of Virology (Fourth Edition), 2021

Abstract

Antigen presentation is a fundamental element of host defense. It encompasses antigen uptake, processing, and brandish together with antigen presenting and costimulatory molecules by a specialized group of leukocytes named antigen-presenting cells. The host immune system is armed with a fragile and complex machinery to expose microbial substances in the optimal context in order to achieve successful activation of specific T and B cells and accomplish pathogen elimination. On the other paw, microorganisms that co-evolved with the host for millions of years use sophisticated maneuvers to interfere with antigen presentation leading to a race between microbe (virulence) and host immune response (resistance) that determines whether the pathogen establishes chronically in the host or is eliminated. In this article, the basic parameters of antigen presentation are reviewed and selective viral strategies to subvert this cornerstone of adaptive amnesty are illustrated.

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Antigen Presentation

J. Waithman , ... J.D. Mintern , in Reference Module in Biomedical Sciences, 2014

Manipulation of Antigen Presentation past Pathogens

Antigen presentation serves to ensure adaptive allowed responses are initiated to invading microorganisms. Therefore, in an effort to survive in the host, pathogens target antigen presentation pathways and disable their function. Impairing antigen presentation enables pathogens to hibernate given that in the absence of functional antigen presentation, T cells can no longer observe pathogen-derived antigen. Indeed this is not only a strategy employed past pathogens, as tumors also manipulate antigen presentation pathways to avert elimination past the immune system.

Targeting the MHC class I antigen presentation pathway is a clever strategy employed by pathogens to avoid an immune response (Hansen and Bouvier, 2009). In particular, viruses that establish intracellular infection can encode proteins with the specific purpose of subverting MHC course I antigen presentation. These proteins target MHC class I antigen presentation at all steps of the pathway, ensuring that viral peptides are no longer displayed for CD8+ T-cell recognition. As such, the major effectors of adaptive immunity tin can no longer detect infected cells. Specific examples of how viruses subvert MHCI antigen presentation will be discussed.

Rendering antigens resistant to proteasomal degradation is a useful strategy to avoid being presented past MHC class I. Such a machinery is employed by EBV virus poly peptide Epstein–Barr virus nuclear antigen ane (EBNA-1) (Levitskaya et al., 1995) and Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen-one (LANA-one) (Zaldumbide et al., 2007). EBNA-i contains long repeats of glycine and alanine residues, while LANA-one contains repetitive acidic sequences rich in glutamine, glutamic acid, and aspartic acid. These stretches of amino acids are considered to interfere with the recognition and unfolding role of the 19S proteasome subunit, thereby protecting these proteins from proteasomal deposition.

Several viral proteins target the TAP peptide transporter. Canker simplex virus-1 ICP47 is a membrane-associated protein that interacts with TAP on its cytoplasmic face (Ahn et al., 1996; Tomazin et al., 1996). The Due north-terminal 32 amino acids of ICP47 blocks peptide binding to TAP past binding with high affinity to the peptide-binding site (Galocha et al., 1997; Neumann et al., 1997). ICP47 also induces a conformational change that destabilizes TAP, turning off ATP hydrolysis (but not ATP binding) and subsequently inhibits peptide translocation into the ER (Lacaille and Androlewicz, 1998). Some other viral protein that exploits the conformational flexibility of TAP is human cytomegalovirus poly peptide US6 (Fruh et al., 1995; Hill et al., 1995). US6 interacts with TAP in the ER lumen and induces a conformational alter that inhibits ATP binding and hydrolysis. Depriving TAP of its energy source, US6 also inhibits MHC class I peptide translocation. In the case of US6, different ICP47, peptide binding to TAP is unaltered. Other proteins that interfere with TAP activity include UL49.five (Koppers-Lalic et al., 2005) and adenovirus E3-19K. E3-19K, a type I transmembrane glycoprotein, binds to TAP, preventing its inclusion into the PLC and inhibits its ability to bridge tapasin and MHC class I (Bennett et al., 1999).

Retaining MHC form I molecules in the ER, virus proteins block MHCI send to the jail cell surface. Adenovirus E3-19K associates with MHC course I, binding to the outer surface of the peptide-binding groove and retains MHC course I in the ER (Andersson et al., 1985; Burgert and Kvist, 1985). Similar to E3-19K, CPXV203 poly peptide encoded by cowpox virus, retains MHC class I in the ER preventing its transport to the plasma membrane (Byun et al., 2007). In improver to only retaining MHC class I in the ER, viruses can likewise promote its removal from the ER for proteasomal degradation. To exercise this, viruses coopt a procedure known as ER-associated degradation (ERAD), where misfolded proteins are removed from the ER. Human cytomegalovirus encodes US2 and US11, type I membrane glycoproteins that both associate with MHC class I and promote its removal from the ER by ERAD. Notably the pathways of ERAD utilized past US2 and US11 differ, with US11 requiring derlin-1 (Ye et al., 2004; Lilley and Ploegh, 2004), while US2 employs a derlin-1-independent ERAD pathway. Murine gamma herpesvirus 68 mK3 is an E3 ligase that binds to TAP and ubiquitinates nascent MHC grade I heavy chains, thereby targeting MHC class I for ERAD (Boname and Stevenson, 2001). HIV Nef diverts the trafficking of MHC class I from the trans-Golgi to an endocytic compartment, preventing it from accessing the jail cell surface (Schwartz et al., 1996; Collins et al., 1998).

Finally, MHC class I that successfully reaches the prison cell surface loaded with viral peptide, is besides subjected to targeting by viral proteins. KSHV encodes K3 and K5 that promote the ubiquitination, and therefore removal, of MHC class I from the cell surface (Coscoy and Ganem, 2000; Ishido et al., 2000). This occurs by clathrin-dependent endocytosis and the subsequent degradation of MHC grade I in lysosomes.

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ANTIGEN PRESENTATION

In Immunology Guidebook, 2004

ANTIGEN PRESENTATION

Antigen presentation is the expression of antigen molecules on the surface of a macrophage or other antigen-presenting prison cell in clan with MHC class 2 molecules when the antigen is being presented to a CD4 + helper T jail cell or in association with MHC class I molecules when presentation is to CD8+ cytotoxic T cells. For appropriate presentation, it is essential that peptides bind securely to the MHC form II molecules, since those that do not bind or are spring but weakly are not presented and fail to elicit an immune response. Following interaction of the presented antigen and MHC class 2 molecules with the CD4+ helper T cell receptor, the CD4+ lymphocyte is activated, IL-2 is released, and IL-2 receptors are expressed on the CD4+ lymphocyte surface. The IL-2 produced by the activated cell stimulates its ain receptors, every bit well as those of mononuclear phagocytes, increasing their microbicidal action. IL-ii besides stimulates B cells to synthesize antibody. Whereas B cells may recognize a poly peptide antigen in its native country, T cells simply recognize the peptides, that issue from antigen processing, in the context of major histocompatibility complex molecules.

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Antigen Presentation and Major Histocompatibility Complex

Pavel P. Nesmiyanov , in Reference Module in Biomedical Sciences, 2020

Abstruse

Antigen presentation is a process that allows T cells to recognize antigenic epitopes displayed on the surface of an antigen-presenting cell. Antigen presentation involves a sophisticated procedure of epitope preparation, i.east., processing which involves cellular machinery designed for full general purposes (e.g., ubiquitination complex and proteasomes) and molecules specific for the presentation pathways. Key molecules providing antigen display are major histocompatibility complex class I and class II which are highly polymorphic and accept many allelic variants. Major part of this molecules is regarded equally initiation of adaptive immunity via recruiting and activation of antigen-specific CD4 and CD8 T cells. Notwithstanding, MHC class I and class II are also essential for T prison cell development and immune tolerance. Antigen processing impairment may result in an autoimmune disease or an immunodeficiency. Pathogens accept evolved multiple immune evasion strategies involving MHC presentation pathways.

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Immunosenescence

Lothar Rink , Inga Wessels , in Reference Module in Biomedical Sciences, 2021

Monocytes, macrophages, and dendritic cells (DC)

Antigen presentation is a prerequisite for activation of the adaptive immune organization. The main antigen presenting cells in the early on allowed response are monocytes/macrophages and dendritic cells (DC), including their tissue resident subtypes. The number of monocytes and DC in the blood of the elderly is equal to that of young adults ( Fulop et al., 2019). In contrast, numbers of skin DC (Langerhans cells) decrease with historic period (Chambers and Vukmanovic-Stejic, 2020). Data on other tissue resident macrophages and DC are rare and not consequent but decreased numbers can be expected as well. In contrast to most other cell types, the monocytes/macrophages of elderly testify an augmented inflammatory response, due east.g., an overproduction of IL-1, IL-6 and other cytokines (meet section "Immune regulation by cytokines"). In dissimilarity to granulocytes, the phagocytic activity of monocytes/macrophages is close to normal. Nevertheless, the antigen presentation and their capability to activate T cells are reduced in monocytes/macrophages and DC (Rich et al., 1993; Agrawal et al., 2007). Pinocytosis and endocytosis reject with age in DC besides. Collectively, the activity of antigen presenting cells is disturbed. However, contempo data signal that the number of MDSC (myeloid-derived suppressor cells) is increased in aging (Verschoor et al., 2013; Alves et al., 2018), which augments the deregulated rest within the myeloid arrangement. Age-related changes in monocytes/macrophages and DC are summarized in Table 4 (Della Bella, 2019).

Table 4. Changes in the function of antigen presenting cells.

Parameter/function Alteration References
Monocytes/macrophages
Number of microglia cells ↑ Wong (2013) ↑
Number of monocytes ↔ Sansoni et al. (1993) ↔, Fagiolo et al. (1993)↔, Franceschi et al. (1995)↔, Cakman et al. (1996) ↔, Cakman et al. (1997) ↔ and Verschoor et al. (2013) ↓
Number of CD14+ monocytes ↘ Nijhuis et al. (1994) ↘
CD68+ cells in os marrow ↘ Ogawa et al. (2000) ↘
Chemotaxis ↔ Gardner et al. (1981) ↔ and Schwab et al. (1985) ↔
Phagocytosis ↔ Gardner et al. (1981) ↔ and Schwab et al. (1985) ↔
Intracellular killing ↔ Gardner et al. (1981) ↔ and Schwab et al. (1985) ↔
Accompaniment function ↘ Rich et al. (1993) ↘
Pro-inflammatory cytokine production ↑ Fagiolo et al. (1993) ↑, Paganelli et al. (1994) ↑, Cakman et al. (1997) ↑ and Gabriel et al. (2002) ↑
Interferon-α production ↓ Kita et al. (1991) ↓, Sindermann et al. (1993) ↓, Uno et al. (1996) ↘ and Cakman et al. (1997) ↓
Expression of adhesion molecule CD11a ↘ Chiricolo et al. (1995) ↘
CD11b ↔ Stohlawetz et al. (1998) ↔ and de Martinis et al. (2000) ↔
CD15 ↔ Stohlawetz et al. (1998) ↔ and de Martinis et al. (2000) ↔
CD29 ↗ Stohlawetz et al. (1998) ↔ and de Martinis et al. (2000) ↔
CD54 ↗ Stohlawetz et al. (1998) ↔ and de Martinis et al. (2000) ↔
CD58 ↔ Rich et al. (1993) ↔ and Fagiolo et al. (1993)↔
Expression of (Fcγ-receptor II) CD32 ↗ Stohlawetz et al. (1998) ↗ and de Martinis et al. (2000) ↗
Expression of HLA-DR ↔ Rich et al. (1993) ↔ and Fagiolo et al. (1993)↔
Myeloid-derived suppressor cells (MDSC)
Number of MDSC ↑ Verschoor et al. (2013) ↑ and Alves et al. (2018) ↗
Monocytic MDSC (CD33+/HLA-DR-) ↘ Verschoor et al. (2013) ↔ and Alves et al. (2018) ↓
Granulocytic MDSC (CD11b+/CD15+) ↑ Verschoor et al. (2013) ↑, Alves et al. (2018) ↑
Dendritic cells (DC)
Number of Langerhans cells ↓ Chambers and Vukmanovic-Stejic (2020) ↓
Number of myeloid (m)DC ↘ Pietschmann et al. (2000) ↔, Perez-Cabezas et al. (2007) ↔, Agrawal et al. (2007)↔, Della Bella et al. (2007)↓, Jing et al. (2009) ↔, Panda et al. (2010) ↔, Garbe et al. (2012) ↔, Orsini et al. (2012) ↓ and Schulz et al. (2015) ↓
Expression of TLR-one,-3,-eight by mDC ↓ Panda et al. (2010) ↓
Number of plasmacytoid (p)DC ↘ Shodell and Siegal (2002) ↓, Perez-Cabezas et al. (2007) ↓, Agrawal et al. (2007) ↔, Della Bella et al. (2007) ↔, Jing et al. (2009) ↓, Panda et al. (2010) ↓, Canaday et al. (2010) ↓, Garbe et al. (2012) ↓, Orsini et al. (2012) ↓ and Schulz et al. (2015)↓
Expression of TLR-9 by pDC ↘ Panda et al. (2010) ↓, Sridharan et al. (2011) ↔ and Garbe et al. (2012) ↓
Expression of TLR-vii pDC ↔ Sridharan et al. (2011) ↔
Interferon-α production by pDC ↓ Jing et al. (2009) ↓, Panda et al. (2010) ↓, Canaday et al. (2010) ↓, Sridharan et al. (2011) ↓ and Qian et al. (2011) ↓
T cell priming by pDC ↓ Agrawal et al. (2007) ↓

Significantly increased ↑, increased ↗, significantly decreased ↓, decreased ↘, normal/unchanged ↔.

Table updated and adjusted from Rink Fifty and Dalhoff Grand (2004) Altersspezifische Veränderungen des Immunsystems und deren assoziierte Krankheitsbilder. In D Ganten, K Ruckpaul and A Ruiz-Torres (eds.), Molekularmedizinische Grundlagen von altersspezifischen Erkrankungen, 1st edn, pp. 429–464, Springer: Berlin. doi:10.1007/978-three-642-18741-4_16 and Della Bella S (2019) Dendritic cells and aging. In T Fulop, C Franceschi, K Hirokawa and G Pawelec (eds.), Handbook of Immunosenescence. 2nd edn, pp. 651–671, Springer International Publishing: Cham. doi:10.1007/978-three-319-99375-1_92.

In conclusion, the defense against all types of pathogens is markedly disturbed in elderly due to the impaired antigen presentation by monocytes/macrophages and DC and the imbalance triggered by an overproduction of pro-inflammatory cytokines and the increased number of MDSC.

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Immunology of Diseases of the Oral Cavity

Stephen J. Challacombe , ... Martin H. Thornhill , in Mucosal Immunology (Fourth Edition), 2015

T-Prison cell Damage to Basal Keratinocytes

Antigen presentation by basal keratinocytes in association with ICAM-one and MHC class I expression will upshot in them existence targeted for cell-mediated allowed destruction ( Sugerman et al., 2000). Evidence for this comes from studies showing increased apoptosis of basal keratinocytes in OLP. Basal keratinocyte apoptosis is observed to be greatest where the T-cell infiltrate is heaviest, where T-cell invasion of the epithelium has occurred, and where basement membrane destruction is most notable (Bloor et al., 1999).

The induction of keratinocyte apoptosis by CD8+ T cells in OLP may occur in several ways. (1) Antigen presentation past basal keratinocytes to antigen-specific cytotoxic T cells may upshot in the keratinocytes becoming the target of prison cell-mediated immune destruction (Traidl et al., 2000). CD95L (Fas ligand) expressing cytotoxic T cells and NK cells may kill their target by bounden CD95 (Fas) on the keratinocyte surface and inducing apoptosis (Thornhill, 2001, 2010). (2) Alternatively, cytotoxic T cells and NK cells can release perforin, which polymerizes to grade holes in the keratinocyte'south prison cell membrane, through which T cells secrete the enzyme granzyme B that breaks downwards intracellular proteins, resulting in keratinocyte cell decease (Kasterlan et al., 2004). At present information technology is not articulate which mechanism is responsible for basal cell damage in OLP and there is some evidence for both. TNFα may also promote apoptosis in OLP. Information technology induces differentiation and activation of cytotoxic T cells, NK cells, and lymphokine-activated killer cells (Lodi et al., 2005). Information technology is as well antiproliferative to keratinocytes and cytotoxic to them at high concentrations. Furthermore, when released directly on to the surface of keratinocyte by adherent cytotoxic T cells, it may straight induce apoptosis by binding the TNFα receptor i on the keratinocyte surface or farther raise Fas/Fas-L-mediated apoptosis (Thornhill, 2010).

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Basic immunology

J. Graham Watson Physician, BSc, FRCPE, FRCP, DCH , A. Graham Bird MD, MRCPath, FRCP , in Handbook of Immunological Investigations in Children, 1990

Cellular immunity

Antigen-specific cellular immunity is generated by specific T lymphocytes and oftentimes also involves the recruitment and activation of non-specific effector cells. In cellular immune responses the effector cells is the monocyte–macrophage and the recruitment factors are the lymphokines (now renamed cytokines) that are released from activated specific T cells. A crucial difference betwixt the T prison cell and the B cell is in the nature of the antigen which it 'recognizes'. Whereas the B cell and its secreted product, antibody, recognizes whole and extracellular antigens, the T lymphocyte is incapable of such recognition and tin can only 'see' small linear peptides of digested protein presented every bit role of a cell membrane and in direct association with the membrane major histocompatibility (MHC) antigens. Antigen presenting cells (macrophages) fulfil a role of poly peptide digestion and presentation in an appropriate form for 'helper' T cells. Whereas antibody tin recognize antigens present in whole bacteria, virus, or parasites, the cytotoxic T cell is incapable of this, only volition identify changes in the jail cell membrane or MHC antigens of infected cells.

The T-cell receptor (for antigen together with MHC proteins) is a 2-chain structure and like immunoglobulin can display a range of specificities due to rearrangement of the Deoxyribonucleic acid in developing T cells. The T-cell receptor recognizes processed peptide antigens (T cells cannot see polysaccharides) in clan with course I (HLA, A, B) or class Ii (HLA DR) MHC antigens. Form I antigens are variably expressed on most nucleated cells whereas class Two antigens are expressed on a limited number of cells well-nigh of which are macrophage or B lymphocyte jail cell types that can process and present antigen.

Antigen presentation consists of the internalization of antigen by pinocytosis, followed by deposition and re-expression of the peptides in close association with class Two MHC molecules. Such peptides are recognized by course 2 restricted lymphocytes bearing T cell receptors, i.e. the response of these lymphocytes is restricted to when they are stimulated past antigen borne by cells bearing class Two (HLA DR) markers. The vast majority of these class II restricted lymphocytes possess helper function and express the CD4 antigen on their membrane. This population of T cells is responsible for release of cytokines, the 3 most important of which are:

Interleukin 2 The major growth gene for T-cell proliferation and a major factor in B-lymphocyte activation.
Interleukin 4 An important mediator of B-jail cell activation and immunoglobulin class switching.
Gamma interferon Responsible for macrophage activation, stimulation of MHC expression, and direct antiviral action. Its enhancement of MHC expression allows more than effective recognition of viral-infected cells by specific T cells.

The other major population of T cells expresses CD8 antigen on their membrane, and is a class I (HLA A, B) restricted population. These cells are non important producers of cytokines, and mediate devastation of virus-infected cells by cytotoxic killing. This population also contains cells capable of suppressing immune responses. Virus-infected cells process peptides derived from the infecting agent and expose these along with class I MHC antigens on their cell membrane. Such cells can be identified as infected and so killed by cytotoxic antigen-specific CD8-positive lymphocytes.

These prerequisites make up one's mind that the T lymphocyte is an important defenct against intracellular infection; a office which antibodies are sick-suited to perform.

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Antigen Presentation Via MHC Class II Molecules

Emil R. Unanue , in Encyclopedia of Immunology (Second Edition), 1998

Cellular events

Antigen presentation takes place very speedily upon entry of antigen into lymphoid tissues. Presumably macrophages and Langerhans-dendritic cells take upwardly the antigen and are responsible for the early recruitment and activation of CD4 T cells. B cells that have surface immunoglobulin molecules with specificity for the antigen as well participate by binding the antigen, processing it and presenting it to the CD4 T cells.

Antigen presentation comprises other events also processing of the antigen and formation of the peptide–MHC complex. First, the antigen-specific T cells must establish physical contact with the APCs. Second, T cells require to interact with two sets of molecules provided by APCs: costimulatory molecules, in society to enter cell wheel and to activate cytokine-specific genes; and cytokines that attune their expression of different genes. Conspicuously T cell activation is a multistage process involving a 'indicate 1', the engagement of the T prison cell receptor, and various 'signal ii'. The molecules that primarily promote concrete contact are termed cell adhesion molecules (or CAMs), while those that primarily promote growth and differentiation are termed costimulators. Details of the APC–T cell interaction are given in the Antigen-Presenting Cell article which contains a tabular array showing the molecules involved.

The interaction between the APCs and the CD4 T cells is physically manifested by shut cell-to-jail cell contact. This intimate APC–CD4 T prison cell contact is favored by cell adhesion molecules the lymphocyte functional antigen-i (LFA-1) on the T cells with its corresponding ligands, ICAM-1, ICAM-ii and ICAM-3 on the APCs; and the CD2 molecule with its counter-receptor. The functional effects of the interaction are reciprocal – macrophages will be stimulated to release cytokines, B cells volition proliferate and differentiate, while the CD4 T cells will also proliferate and release cytokines.

Costimulator molecules are key in determining that the engagement of the T cell antigen receptor to the MHC–peptide circuitous is a productive interaction. These include the B7-1 and B7-2 molecules on APCs (and their coreceptors CD28 and CTLA-4 on T cells), and the CD40 molecule on B cells in particular, and the CD40 ligand coreceptors on T cells. These costimulator molecules may human activity past inducing early release past T cells of growth factors such as interleukin-2 (IL-ii) and/or past regulating the expression of receptors for growth factors, and by inhibiting apoptosis. In vitro experiments indicate that exposure of T cells to fixed APCs (which cannot provide costimulatory molecules) results in an absent-minded response. Such T cells, in fact, may develop an unresponsive or anergic state. Costimulatory molecules of APCs are expressed in low amounts. The representation of their expression is one component that initiates productive presentation. Finally to notation is that several cytokines from APCs attune the T jail cell response during antigen presentation. Included are IL-1α and β, tumor necrosis gene -α (TNFα), IL-6 and IL-12. This latter cytokine is key in the differentiation of T cells to the THone subset.

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Immunity and Resistance to Viruses

Susan Payne , in Viruses, 2017

Antigen Presentation

Antigen presentation is central to specific immunity. Extracellular antigens can bind to professional antigen presenting cells (APCs) (macrophage, dendritic cells, and B cells). Viral (or other) antigens produced inside of cells are proteolytically candy and are presented on the surface of the cell. Antigens are presented by a set of prison cell surface proteins called major histocompatibility (MHC) proteins (Fig. 6.vi). Their chief function is to demark peptide fragments and brandish them on the cell surface for recognition past the advisable T cells. All cells produce MHC class I molecules and these demark to fragments of jail cell proteins (self) or peptides derived from intracellular pathogens (nonself). APCs express MHC class II proteins.

Effigy 6.half-dozen. MHC proteins bind and nowadays both "self" and "foreign" peptides.

An APC takes upwardly extracellular antigen, processes it, and returns small-scale peptides to the cell surface, spring to an MHC class Two protein. Cells that present foreign antigens in the context of MHC can be recognized by antigen-sensitive cells such as CD8+ and CD4+ T cells. Cytotoxic CD8+ T cells recognize peptides on MHC course I molecules and CD4+ T cells recognize peptides bounden to MHC class II molecules.

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AVIAN ANTIGEN PRESENTING CELLS

BERND KASPERS , ... COLIN BUTTER , in Avian Immunology, 2008

INTRODUCTION

Antigen Presentation

Antigen presentation is the mechanism by which the antigenic environment is sampled and information imparted to the effector artillery of the adaptive allowed arrangement, B and T lymphocytes. Depending on the precise context, antigen presentation can result in either activation or tolerization of lymphocytes, corresponding examples being the response to a pathogen challenge or tolerance to self-antigen. An antigen is subjected to either endogenous or exogenous processing and the resulting peptides are expressed on the surface of the antigen presenting cell (APC) spring to either major histocompatibility complex (MHC) class I or II molecules (see Chapter 8). The type of MHC molecule involved in the presentation not just reflects the source of the antigen, only too has the primary role in determining the ensuing immune response to it.

Virtually all cells express course I heterodimer molecules on their outer surface and use the specialized MHC peptide binding cleft to express peptides derived from endogenous antigens, sampled from the cytoplasm or nucleus. The avian MHC region and the proteins it encodes are described in detail in Affiliate 8. Endogenous processing degrades the host'southward own proteins, tumour antigens if a prison cell has been neoplastically transformed or antigens derived from pathogens, which replicate within the cytoplasm or nucleus. These proteins are degraded to peptides past the proteasome, and the peptides are translocated to the endoplasmic reticulum where they become bound to MHC course I molecules. The peptide stabilizes the MHC molecular complex which is transported to the prison cell surface via the Golgi apparatus. If an MHC molecule bearing a peptide derived from a strange or transformed antigen is expressed on the cell surface, the antigen–MHC complex is recognized past a T cell receptor (TCR) on a CD8+ jail cell. The MHC/TCR interaction induces the CD8+ cell to proliferate and become armed antigen-specific cytotoxic T lymphocytes (CTL). Activated CTL are able to kill other cells presenting the aforementioned antigen on their surface in the context of MHC form I. In this manner, virally-infected or transformed cells are killed, thereby limiting their farther replication or spread of the pathogen.

Exogenous antigen can exist phagocytosed by specialized APC such as macrophages, or taken upwards by dendritic cells (DC) and B cells by receptor-mediated absorptive endocytosis, or by DC through macropinocytosis. These exogenous antigens reside within endosomes. Too included hither are antigens derived from pathogens, such every bit Salmonella, which invade APC and reside within intracellular vesicles. The endosome fuses with a lysosome-containing acid proteases to form a phagolysosome and this results in the digestion of the exogenous antigens into antigenic peptides. Peptide-containing phagolysosomes fuse with other vesicles which comprise the α and β bondage of the MHC class II molecule, in the process replacing a stabilizing invariant concatenation, so that the antigen peptide can be transported to, and presented on, the surface of the cell in the context of the MHC course Two molecule. DC are able to place class Two MHC–antigen complexes on their surfaces at far higher densities than is doable by macrophages. DC reach this past means of the production of subcellular compartments rich in MHC molecules which fuse with the antigen-rich endocytotic vesicles. Antigen–MHC complexes are recognized on the prison cell surface by the TCR of CD4+ T cells, which then activate other immune effector cells. B cells presenting antigen using MHC class Two molecules are induced to secrete antigen-specific antibody by interaction with activated CD4+ Th2 cells of the same specificity. Macrophages harbouring intravesicular leaner or parasites can be activated and induced to kill them past interaction with Th1 cells. DC too have the ability to load peptides generated in the endosomal pathway onto MHC class I molecules. Although the molecular mechanisms that facilitate this are not fully elucidated, the resulting miracle, called cross-priming, ensures that viral infections are able to generate both CTL and humoral responses, irrespective of their site of replication. Co-stimulation, discussed in Chapter 4 in the context of B cells, is essential for the generation of allowed response. T cells recognizing antigen on the surface of a DC – in the context of the MHC molecule and co-stimulation – are induced into proliferation and differentiation into effector T cells. T cells recognizing the antigen–MHC complex in the absence of a "second signal" become anergic, fifty-fifty in the face of further stimulation by DC.

Dendritic Cells

Since their identification over 30 years ago, DC, the most potent APC that are able to stimulate naïve T cells in antigen-specific immune response, have been cardinal to the study of immune responses in mammalian species (Steinman et al., 1975 ). The existence of a specialist APC in birds has long been speculated but until recently evidence was mostly circumstantial. Of the three types of mammalian professional APC: B cells, macrophages and DC, the outset one tin be excluded every bit being necessary for antigen presentation since bursectomized birds, lacking in B cells, can mountain normal T prison cell responses ( Aggravate et al., 2006). The possibility remains that avian macrophages may exist sufficient to mount normal immune responses. Nevertheless, it is only with (1) the recent appearance of recombinant cytokines, (2) the development of isolation protocols and (3) the generation of DC-relevant antibodies that studies on avian DC equally a singled-out population accept been possible. Although only now we are attaining an understanding of avian DC biology, it is already apparent that many of the characteristics of mammalian DC – a prerequisite to their unique function – are replicated in whole or in role in birds. Whilst much of the molecular machinery which allows DC to present antigen has been described for the chicken (run across Chapter eight), this is not of itself sufficient to ascertain an immune surveillance system. The acts of antigen uptake, processing and presentation identify different requirements on the APC, resulting in a change of country from the and so-called immature phenotype, which is efficient at antigen capture, to the "mature" phenotype that is optimal for antigen presentation. Furthermore, antigen capture may take place at a site which is anatomically distant from where antigen presentation to lymphocytes occurs; and DC must therefore as well take, or acquire, the ability to selectively drift. These issues are discussed later.

Macrophages

Macrophages represent a heterogeneous group of cells which are found throughout the body in both vertebrates and invertebrates (Gordon and Taylor, 2005). The term macrophage was introduced in 1884 by Ilya Metchnikoff to describe leukocytes which are capable of ingesting and destroying foreign substances including micro-organisms (Karnovsky, 1981). Since then it has go clear that these cells play a fundamental function in tissue homeostasis, innate and caused immunity, and inflammation and immunopathology (Gordon, 2003). To accomplish this multiplicity of tasks, macrophages detect environmental signals through specific receptors, phagocytose apoptotic and necrotic cells as well as invading micro-organisms, and answer to these stimuli by the secretion of signalling and effector molecules. Much progress has been made in the field of macrophage biological science in recent years past definition of the structure and function of their molecules in some mammalian species (Taylor et al., 2005). By comparison, knowledge on avian macrophages is very limited and the number of macrophage-specific tools is restricted. Here, we will give an overview of avian macrophage biology.

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