1Vertebrate adaptive immune cells posss two types of antigen receptors: the immunoglobulins that rve as antigen receptors on B cells, and the T-cell receptors. While immunoglobulins can recognize native antigens, T cells rec-ognize only antigens that are displayed by MHC complexes on cell surfaces. The conventional α:β T cells recognize antigens as peptide:MHC complexes (e Section 4-13). The peptides recognized by α:β T cells can be derived from the normal turnover of lf proteins, from intracellular pathogens, such as virus, or from products of pathogens taken up from the extracellular fluid. Various tolerance mechanisms normally prevent lf peptides from initiating an immune respon; when the mechanisms fail, lf peptides can become the target of autoimmune respons, as discusd in Chapter 15. Other class of T cells, such as MAIT cells and γ:δ T cells (e Sections 4-18 and 4-20), rec-ognize different types of surface molecules who expression may indicate infection or cellular stress.
The first part of this chapter describes the cellular pathways ud by various types of cells to generate peptide:MHC complexes recognized by α:β T cells. This process participates in adaptive immunity in at least two different ways. In somatic cells, peptide:MHC complexes can signal the prence of an intra-cellular pathogen for elimination by armed effector T cells. In dendritic cells, which may not themlves be infected, peptide:MHC complexes rve to acti-vate antigen-specific effector T cells. We will also int
roduce mechanisms by which certain pathogens defeat adaptive immunity by blocking the produc-tion of peptide:MHC complexes.
The cond part of this chapter focus on the MHC class I and II genes and their tremendous variability. The MHC molecules are encoded within a large cluster of genes that were first identified by their powerful effects on the immune respon to transplanted tissues and were therefore called the major histocompatibility complex (MHC). There are veral different MHC mole-cules in each class, and each of their genes is highly polymorphic, with many variants prent in the population. MHC polymorphism has a profound effect on antigen recognition by T cells, and the combination of multiple genes and polymorphism greatly extends the range of peptides that can be prented to T cells in each individual and in populations as a whole, thus enabling indi-viduals to respond to the wide range of potential pathogens they will encoun-ter. The MHC also contains genes other than tho for the MHC molecules; some of the genes are involved in the processing of antigens to produce pep-tide:MHC complexes.
The last part of the chapter discuss the ligands for unconventional class of T cells. We will examine a group of proteins similar to MHC class I mole-cules that have limited polymorphism, some encoded within the MHC and others encoded outside the MHC. The so-called nonclassical MHC c
lass I proteins rve various functions, some acting as ligands for γ:δ T-cell receptors and MAIT cells, or as ligands for NKG2D expresd by T cells and NK cells. In addition, we will introduce a special subt of α:β T cells known as invariant NKT cells that recognize microbial lipid antigens prented by the proteins.Antigen Prentation to
T Lymphocytes
6IN THIS CHAPTER The generation of α:β T -cell receptor ligands.The major histocompatibility complex and its function.Generation of ligands for unconventional T -cell subts.
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The generation of α:β T-cell receptor ligands.骨的构造
The protective function of T cells depends on their recognition of cells har-boring intracellular pathogens or that have internalized their products. As we saw in Chapter 4, the ligand recognized by an α:β T-cell receptor is a peptide bound to an MHC molecule and displayed on a cell surface. The generation of peptides from native proteins is commonly referred to as antigen processing, while pep
tide display at the cell surface by the MHC molecule is referred to as antigen prentation. We have already described the structure of MHC mole-cules and en how they bind peptide antigens in a cleft, or groove, on their outer surface (e Sections 4-13 to 4-16). We will now look at how peptides are generated from the proteins derived from pathogens and how they are loaded onto MHC class I or MHC class II molecules.
6-1Antigen prentation functions both in arming effector T cells and in triggering their effector functions to attack pathogen-
infected cells.
The processing and prentation of pathogen-derived antigens has two distinct purpos: inducing the development of armed effector T cells, and triggering the effector functions of the armed cells at sites of infection. MHC class I molecules bind peptides that are recognized by CD8 T cells, and MHC class II molecules bind peptides that are recognized by CD4 T cells, a pattern of rec-ognition determined by specific binding of the CD8 or CD4 molecules to the respective MHC molecules (e Section 4-18). The importance of this specific-ity of recognition lies in the different distributions of MHC class I and class II molecules on cells throughout the body. Nearly all somatic cells (except red
blood cells) express MHC class I molecules. Conquently, the CD8 T cell is primarily responsible for pathogen surveillance and cytolysis of somatic cells. Also called cytotoxic T cells, their function is to kill the cells they recognize. CD8 T cells are therefore an important mechanism in eliminating sources of new viral particles and bacteria that live only in the cytosol, and thus freeing the host from infection.
By contrast, MHC class II molecules are expresd primarily only on cells of the immune system, and particularly by dendritic cells, macrophages, and B cells. Thymic cortical epithelial cells and activated, but not naive, T cells can express MHC class II molecules, which can also be induced on many cells in respon to the cytokine IFN-γ. Thus, CD4 T cells can recognize their cognate antigens during their development in the thymus, on a limited t of ‘profes-sional’ antigen-prenting cells, and on other somatic cells under specific inflammatory conditions. Effector CD4 T cells compri veral subts with different activities that help eliminate the pathogens. Importantly, naive CD8 and CD4 T cells can become armed effector cells only after encountering their cognate antigen once it has been procesd and prented by activated den-dritic cells.
属龙的命运In considering antigen processing, it is important to distinguish between the various cellular compartments from which antigens can be derived (Fig. 6.1). The compartments, which are par
ated by membranes, include the cytosol and the various vesicular compartments involved in endocytosis and cre-tion. Peptides derived from the cytosol are transported into the endoplasmic reticulum and directly loaded onto newly synthesized MHC class I molecules on the same cell for recognition by T cells, as we will discuss below in greater detail. Becau virus and some bacteria replicate in the cytosol or in the contiguous nuclear compartment, peptides from their components can be loaded onto MHC class I molecules by this process (Fig. 6.2, first upper panel).
3
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The generation of α:β T -cell receptor ligands.This pathway of recognition is sometimes referred to a
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s direct prenta-tion , and can identify both somatic and immune cells that are infected by a pathogen.
Certain pathogenic bacteria and protozoan parasites survive ingestion by macrophages and are able to replicate inside the intracellular vesicles of the endosomal–lysosomal system (Fig. 6.2, cond panel). Other pathogenic bacteria proliferate outside cells, and can be internalized, along with their toxic products, by phagocytosis, receptor-mediated endocytosis, or macro-pinocytosis into endosomes and lysosomes, where they are broken down by digestive enzymes. For example, receptor-mediated endocytosis by B cells can efficiently internalize extracellular antigens through B-cell receptors (Fig. 6.2, third panel). Virus particles and parasite antigens in extracellular fluids can also be taken up by the routes and degraded, and their peptides prented to T cells.
Some pathogens may infect somatic cells but not directly infect phagocytes such as dendritic cells. In this ca, dendritic cells must acquire antigens from exogenous sources in order to process and prent antigens to T cells. For example, to eliminate a virus that infects only epithelial cells, activation of CD8 T cells will require that dendritic cells load MHC class I molecules with peptides derived from viral proteins taken up from virally infected cells. This exogenous pathway of loading MHC class I molecules is called cross- prentation , and is carried out very efficiently by some spec
ialized types of dendritic cells (Fig. 6.3). The activation of naive T cells by this pathway is called cross-priming
.
Fig. 6.1 There are two categories of major intracellular compartments, parated
by membranes. One compartment is the cytosol, which communicates with the nucleus
via pores in the nuclear membrane. The other is the vesicular system, which compris the endoplasmic reticulum, Golgi apparatus, endosomes, lysosomes, and other intracellular
vesicles. The vesicular system can be thought of as being continuous with the extracellular fluid. Secretory vesicles bud off from the endoplasmic reticulum and are transported via
fusion with Golgi membranes to move vesicular contents out of the cell. Extracellular material is taken up by endocytosis or phagocytosis into endosomes or phagosomes, respectively. The fusion of incoming and outgoing vesicles is important both for pathogen destruction
in cells such as neutrophils and for antigen prentation. Autophagosomes surround
components in the cytosol and deliver them to lysosomes in a process known as autophagy.Fig. 6.2 Cells become targets of T -cell recognition by acquiring antigens from either the cytosolic or the vesicular compartments. Top, first panel: virus and some bacteria replicate in the cytosolic compartment. Their antigens are prented by MHC class I molecules to activate killing by cytotoxic CD8 T cells. Second panel: other bacteria and some parasites are taken up into endosomes, usually by specialized phagocytic cells such as macrophages. Here they are killed and degraded, or in some
cas are able to survive and proliferate within the vesicle. Their antigens are prented by MHC class II molecules to activate cytokine production by CD4 T cells. Third panel: proteins derived from extracellular pathogens may bind to cell-surface receptors and enter the vesicular system by endocytosis, illustrated here for antigens bound by the surface immunoglobulin of B cells. The antigens are prented by MHC class II molecules to CD4 helper T cells, which can then
stimulate the B cells to produce antibody.
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For loading peptides onto MHC class II molecules, dendritic cells, macro-phages, and B cells are able to capture exogenous proteins via endocytic ves-icles and through specific cell-surface receptors. For B cells, this process of antigen capture can include the B-cell receptor. The peptides that are derived from the proteins are loaded onto MHC class II molecules in specially mod-ified endocytic compartments in the antigen-prenting cells, which we will discuss in more detail later. In dendritic cells, this pathway operates to activate naive CD4 T cells to become effector T cells. Macrophages take up particulate material by phagocytosis and so mainly prent pathogen-derived peptides on MHC class II molecules. In macrophages, such antigen prentation may be ud to ind
icate the prence of a pathogen within its vesicular compartment. Effector CD4 T cells, on recognizing antigen, produce cytokines that can acti-vate the macrophage to destroy the pathogen. Some intravesicular pathogens have adapted to resist intracellular killing, and the macrophages in which they live require the cytokines to kill the pathogen: this is one of the roles of the T H 1 subt of CD4 T cells. Other CD4 T cell subts have roles in regulating other aspects of the immune respon, and some CD4 T cells even have cyto-toxic activity. In B cells, antigen prentation may rve to recruit help from CD4 T cells that recognize the same protein antigen as the B cell. By efficiently endocytosing a specific antigen via their surface immunoglobulin and pre-nting the antigen-derived peptides on MHC class II molecules, B cells can activate CD4 T cells that will in turn rve as helper T cells for the production of antibodies against that antigen.Beyond the prentation of exogenous proteins, MHC class II molecules can also be loaded with peptides derived from cytosolic proteins by a ubiquitous pathway of autophagy , in which cytoplasmic proteins are delivered into the endocytic system for degradation in lysosomes (Fig. 6.4). This pathway can rve in the prentation of lf-cytosolic proteins for the induction of toler-ance to lf antigens, and also as a means for prenting antigens from patho-gens, such as herpes simplex virus, that have accesd the cell’s cytosol.6-2 Peptides are generated from ubiquitinated proteins in the cytosol by the proteasome.Proteins in cells are continually being degraded and replaced with newly syn-thesize
d proteins. Much cytosolic protein degradation is carried out by a large, multicatalytic protea complex called the proteasome (Fig. 6.5). A typical proteasome is compod of one 20S catalytic core and two 19S regulatory caps , one at each end; both the core and the caps are multisubunit complexes of proteins. The 20S core is a large cylindrical complex of some 28 subunits, arranged in four stacked rings of ven subunits each around a hollow core. The two outer rings are compod of ven distinct α subunits and are noncat-alytic. The two inner rings of the 20S proteasome core are compod of ven distinct β subunits. The constitutively expresd proteolytic subunits are β1, β2, and β5, which form the catalytic chamber. The 19S regulator is compod of a ba containing nine subunits that binds directly to the α
ring of the 20S
Fig. 6.3 Cross-prentation of extracellular antigens on MHC class I molecules by dendritic cells. Certain subts of dendritic cells are efficient in capturing exogenous proteins and loading peptides derived from them onto MHC class I molecules. There is evidence that veral cellular pathways may be involved. One route may involve the translocation of ingested proteins from the phagolysosome into the cytosol for degradation by the proteasome, with the resultant peptides then passing through TAP (e Section 6-3) into the endoplasmic reticulum, where they load onto MHC class I molecules in the usual way. Another route may involve direct transport of antigens from the phagolysosome into a vesicular loading compartment—without passage through the cytosol—where peptides are allowed to be bound to mature MHC class I molecules.
Fig. 6.4 Autophagy pathways
can deliver cytosolic antigens
for prentation by MHC class II
molecules. In the process of autophagy,
portions of the cytoplasm are taken into
autophagosomes, specialized vesicles
透明色that are fud with endocytic vesicles
生日快乐的诗句and eventually with lysosomes, where
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the contents are catabolized. Some of
the resulting peptides of this process can
be bound to MHC class II molecules and
prented on the cell surface. In dendritic
cells and macrophages, this can occur in
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the abnce of activation, so that immature
dendritic cells may express lf peptides in
a tolerogenic context, rather than inducing
T -cell respons to lf antigens.
5 The generation of α:β T-cell receptor ligands.
core particle and a lid that has up to 10 different subunits. The association of the 20S core with a 19S cap requires ATP as well as the ATPa activity of many of the caps’ subunits. One of the 19S caps binds and delivers proteins into the proteasome, while the other keeps them from exiting prematurely.
Proteins in the cytosol are tagged for degradation via the ubiquitin–proteasome system (UPS). This
begins with the attachment of a chain of veral ubiquitin molecules to the target protein, a process called ubiquitination. First, a lysine residue on the targeted protein is chemically linked to the glycine at the carboxy terminus of one ubiquitin molecule. Ubiquitin chains are then formed by linking the lysine at residue 48 (K48) of the first ubiquitin to the carboxy-terminal glycine of a cond ubiquitin, and so on until at least 4 ubiquitin molecules are bound. This K48-linked type of ubiquitin chain is recognized by the 19S cap of the proteasome, which then unfolds the tagged protein so that it can be introduced into the proteasome’s catalytic core. There the protein chain is degraded with a general lack of quence specificity into short peptides, which are subquently relead into the cytosol. The general degradative functions of the proteasome have been co-opted for antigen prentation, so that MHC molecules have evolved to work with the peptides that the proteasome can produce.
Various lines of evidence implicate the proteasome in the production of pep-tide ligands for MHC class I molecules. Experimentally tagging proteins with ubiquitin results in more efficient prentation of their peptides by MHC class I molecules, and inhibitors of the proteolytic activity of the proteasome inhibit antigen prentation by MHC class I molecules. Whether the proteas-ome is the only cytosolic protea capable of generating peptides for transport into the endoplasmic reticulum is not known.
The constitutive β1, β2, and β5 subunits of the catalytic chamber are sometimes replaced by three alternative catalytic subunits that are induced by interferons. The induced subunits are called β1i (or LMP2), β2i (or MECL-1), and β5i (or LMP7). Both β1i and β5i are encoded by the PSMB9 and PSMB8 genes, which are located in the MHC locus, whereas β2i is encoded by PSMB10 outside the MHC locus. Thus, the proteasome can exist both as both a constitutive proteasome prent in all cells and as the immunoproteasome, which is prent in cells stimulated with interferons. MHC class I proteins are also induced by interferons. The replacement of the β subunits by their interferon-inducible counterparts alters the enzymatic specificity of the proteasome such that there is incread cleavage of polypeptides after hydrophobic residues, and decread cleavage after acidic residues. This produces peptides with carboxy-terminal residues that are preferred anchor residues for binding to most MHC class I molecules (e Chapter 4) and are also the preferred structures for transport by TAP.
Another substitution for a β subunit in the catalytic chamber has been found to occur in cells in the thymus. Epithelial cells of the thymic cortex (cTECs) express a unique β subunit, called β5t, that is encoded by PSMB11. In cTECs, β5t becomes a component of the proteasome in association with β1i and β2i,
and this specialized type of proteasome is called the thymoproteasome. Mice lacking expression of β5t have reduced numbers of CD8 T cells, indicating that the peptide:MHC complexes produced by the thymoproteasome are impor-tant in CD8 T-cell development in the thymus.
Interferon-γ (IFN-γ) can further increa the production of antigenic pep-tides by inducing expression of the PA28 proteasome-activator complex that binds to the proteasome. PA28 is a six- or ven-membered ring compod of two proteins, PA28α and PA28β, both of which are induced by IFN-γ. A PA28 ring, which can bind to either end of the 20S proteasome core in place of the 19S regulatory cap, acts to increa the rate at which peptides are relead (Fig. 6.6). In addition to simply providing more peptides, the incread rate of
Fig. 6.5Cytosolic proteins are degraded by the ubiquitin–proteasome system into short peptides. The proteasome is compod of a 20S catalytic core, which consists of four multisubunit rings (e text), and two 19S regulatory caps on either end. Proteins (orange) that are targeted become covalently tagged with K48-linked polyubiquitin chains (yellow) through the actions of various E3 ligas. The 19S regulatory cap recognizes polyubiquitin and draws the tagged protein inside the catalytic chamber; there, the protein is degraded, giving ri to small peptide fragments that are relead back into the cytoplasm.
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