T Cell Recognition Of A Peptide – MHC Complex PDF

T cell recognition of a peptide – MHC complex  The function of MHC molecules is to bind and display peptides for recognition by CD4+...

T cell recognition of a peptide – MHC complex  The function of MHC molecules is to bind and display peptides for recognition by CD4+ and CD8+ T cells  MHC recognition is also required for the maturation of T cells, ensuring that mature T cells are restricted to recognizing only MHC molecules with bound antigens  MHC molecules are highly polymorphic, and variations in MHC molecules among individuals influence both peptide binding and T cell recognition.  Antigen presenting cells (APC) capture antigens from its site of entry or production and bring it to the lymphoid organs where naïve T lymphocytes are located.  Major histocompatibility complex (MHC) molecules are on cells identifying as self or non-self. There are two classes of MHC molecules  MHC I found on all nucleated cells; MHC II found on macrophages, dendritic cells and B cells. 2 Major histocompatibility complex (MHC) 3  Properties of Antigen Presenting Cells (APC)  APC is the term used to refer to specialized cells that display antigens to lymphocytes.  APCs express class II MHC molecules and other molecules involved in stimulating T cells and are capable of activating CD4+ T lymphocytes.  Dendritic cells  Most effective APCs for activating naïve T cells and therefore for initiating T cell responses.  Macrophages and B lymphocytes; great for previously activated CD4+ helper T cells rather than for naïve T cells 4  Functions of APC  Antigen is the first signal for the activation of naïve T cells, the additional stimuli that also activate naïve T cells are called second signals  Co-stimulators are membrane bound molecules of APCs that function together with antigens to stimulate T cells  Adjuvants are products of microbes, that enhance the expression of co-stimulators and cytokines and also stimulate the antigen- presenting functions of APCs. 5 Properties and Functions of APCs 6  Role of Dendritic Cells  Some antigens are transported in the lymph by APCs (primarily DCs) that capture the antigen and enter lymphatic vessels.  Antigens that enter the bloodstream may be sampled by DCs that are in the spleen, or captured by circulating DCs and taken to the spleen.  Resting tissue-resident DCs use receptors to capture, such as C-type lectins, that bind and endocytose microbes or microbial proteins and then process the ingested proteins into peptides capable of binding to MHC molecules.  DCs can ingest antigens by pinocytosis, a process that does not involve specific recognition receptors but serves to internalize whatever molecules might be in the fluid phase in the vicinity of the DCs.  The DCs are activated by cytokines, such as tumor necrosis factor (TNF), produced in response to the microbes. The activated DCs (also called mature DCs) lose their adhesiveness for epithelia or tissues and begin to express a chemokine receptor called CCR7 that is specific for two chemokines, CCL19 and CCL21, that are produced in lymphatic vessels and in the T cell zones of lymph nodes. 7  Role of dendritic cells in antigen capture and presentation  DCs are strategically located at the common sites of entry of microbes and foreign antigens (in epithelia) and in tissues that may be colonized by microbes. DCs express receptors that enable them to capture and respond to microbes.  DCs migrate from epithelia and tissues via lymphatics, preferentially into the T cell zones of lymph nodes, and naive T lymphocytes also circulate through the same regions of the lymph nodes.  Mature DCs express high levels of peptide-MHC complexes, co- stimulators, and cytokines, all of which are needed to activate naive T lymphocytes. 8 Major Histocompatibility Complex Discovery  If a mouse is infected with a virus, CD8+ T cells specific for the virus are activated and differentiate into CTLs in the animal. When the function of these CTLs is analyzed in vitro, they recognize and kill virus-infected cells only if the infected cells express MHC molecules that are expressed in the animal from which the CTLs were removed.  T cells must be specific not only for the antigen but also for MHC molecules, and T cell antigen recognition is restricted by the MHC molecules a T cell sees. 9 MHC Genes  The polymorphic class I and class II MHC molecules are the ones whose function is to display peptide antigens for recognition by CD8+ and CD4+ T cells, respectively.  The products of different MHC alleles bind and display different peptides, different individuals in a population may present different peptides even from the same protein antigen.  For a given MHC gene, each individual expresses the alleles that are inherited from both parents. For the individual, this maximizes the number of MHC molecules available to bind peptides for presentation to T cells. 10 Map Of The Human MHC Genes  In humans, the MHC is located on the short arm of chromosome 6 and occupies a large segment of DNA, extending about 3500 kilobases (kb)  There are three class I MHC genes called HLA-A, HLA-B, and HLA-C, which encode three types of class I MHC molecules with the same names.  There are three class II HLA gene loci called HLA-DP, HLA-DQ, and HLA-DR. Each class II MHC molecule is composed of a heterodimer of α and β polypeptides.  The set of MHC alleles present on each chromosome is called an MHC haplotype. 11 MHC molecule expression  Class I molecules are expressed on all nucleated cells  They provide a display system for viral and tumor antigens, so these antigens can be recognized by CTLs and the antigen-producing cells can be killed  Class I molecule expression is increased by the type I interferons IFN- and IFN- , which are produced during the early and innate immune response to many viruses  Class II molecules are expressed only on dendritic cells, B lymphocytes, macrophages, thymic epithelial cells ad a few other cell types  Class II molecules are regulated by cytokines and other signals in different cells. IFN- is the principal cytokine involved in the stimulating expression of class II molecules in APCs such as DCs and macrophages.  IFN- provides a mechanism by which innate immunity promotes adaptive immunity, by increasing class II MHC expression on APCs, and provides an amplification mechanism in adaptive immunity. 12 Enhancement of class II MHC molecule expression by interferon-γ  IFN-γ, produced by NK cells and other cell types during innate immune reactions to microbes or by T cells during adaptive immune reactions, stimulates class II MHC expression on APCs and thus enhances the activation of CD4+ T cells.  IFN-γ and type I interferons have a similar effect on the expression of class I MHC molecules and the activation of CD8+ T cells. 13  Structure of MHC Molecules Each MHC molecule consists of an extracellular peptide-binding cleft, followed by an immunoglobulin (Ig)–like domain and transmembrane and cytoplasmic domains. The polymorphic amino acid residues of MHC molecules are located in and adjacent to the peptide-binding cleft. The nonpolymorphic Ig-like domains of class II and class I MHC molecules contain binding sites for the T cell molecules CD4 and CD8, respectively 14  Class I MHC Molecules  Class I molecules are composed of a polymorphic α chain noncovalently attached to the nonpolymorphic β2- microglobulin (β2m).  The ribbon diagram (right) shows the structure of the extracellular portion of the HLA-B27 molecule with a bound peptide. 15  Class II MHC Molecules  Class II molecules are composed of a polymorphic α chain noncovalently attached to a polymorphic β chain.  The ribbon diagram (right) shows the structure of the extracellular portion of the HLA-DR1 molecule with a bound peptide. 16 Polymorphic residues of MHC molecules  The polymorphic residues of class I molecules are confined to the α1 and α2 domains, where they contribute to variations among different class I alleles in peptide binding and T cell recognition.  The polymorphic residues of class II molecules are located in the α1 and β1 segments, in and around the peptide- binding cleft, as in class I MHC molecules 17  Peptide binding to MHC molecules  The class I molecule shown is HLA-A2, and the class II molecule is HLA-DR1. The cleft of the class I molecule is closed, whereas that of the class II molecule is open. As a result, class II molecules accommodate longer peptides than class I molecules. B, The side view of a cutout of a peptide bound to a class II MHC molecule shows how anchor residues of the peptide hold it in the pockets in the cleft of the MHC molecule. 18  The mechanisms of antigen processing are designed to generate peptides that have the structural Processing of Protein Antigens characteristics required for associating with MHC molecules, and to place these peptides in the same cellular location as newly synthesized MHC proteins with available peptide-binding clefts.  Proteins that are present in the cytosol are degraded by proteasomes to yield peptides that are displayed on class I MHC molecules, while proteins that are ingested from the extracellular environment and sequestered in vesicles are degraded in lysosomes (or late endosomes) to generate peptides that are presented on class II MHC molecules 19 The Class I MHC Pathway for Processing and Presentation of Cytosolic Proteins Microbial proteins present in the cytosol that undergo proteasomal degradation are derived from microbes (typically viruses) that replicate and survive in the cytosol of cells, extracellular bacteria that inject proteins into the cytosol, and various extracellular organisms that are phagocytosed and their proteins are transported from vesicles into the cytosol Degradation of proteins in proteasomes generates peptides that are able to bind to class I MHC molecules. Peptides generated by proteasomes in the cytosol are translocated by a specialized transporter into the ER, where newly synthesized class I MHC molecules are available to bind the peptides. This delivery is mediated by a dimeric protein located in the ER membrane called transporter associated with antigen processing (TAP) Class I MHC molecules with bound peptides are structurally stable and are expressed on the cell surface. 20 The Class I MHC Pathway for Processing and Presentation of Cytosolic Proteins 21 Comparative Features of Class I and Class II Major Histocompatibility Complex Pathways of Antigen Processing and Presentation 22  The Class II MHC Pathway for Presentation of Proteins Degraded in Lysosomes Most class II MHC–associated peptides are derived from protein antigens that are digested in endosomes and lysosomes in APCs Internalized proteins are degraded enzymatically in late endosomes and lysosomes to generate peptides that are able to bind to the peptide-binding clefts of class II MHC molecules. 23 Biosynthesis and Transport of Class II MHC Molecules  Class II MHC molecules are synthesized in the ER and transported to endosomes with an associated protein, the invariant chain (Ii), which occupies the peptide-binding clefts of the newly synthesized class II MHC molecules  Within the endosomal vesicles, the Ii dissociates from class II MHC molecules by the combined action of proteolytic enzymes and the HLA-DM molecule, and peptides derived from protein antigens are then able to bind to the available peptide-binding clefts of the class II molecules  The DM molecule also edits the repertoire of peptides being presented, favoring the display of peptides that bind to class II MHC molecules with high affinity  Class II MHC molecules are stabilized by the bound peptides, and the stable peptide–class II complexes are delivered to the surface of the APC, where they are displayed for recognition by CD4+ T cells. 24 Biosynthesis and Transport of Class II MHC Molecules to Endosomes 25  Nature of Effector T Cell Responses Cells infected with intracellular microbes, such as viruses, are ingested by dendritic cells, and the antigens of the infectious microbes are transported into the cytosol and processed in proteasomes and presented in association with class I MHC molecules to CD8+ T cells. Dendritic cells are able to present endocytosed vesicular antigens by the class I pathway. Note that the same cross-presenting APCs may display class II MHC–associated antigens from the microbe for recognition by CD4+ helper T cells 26 Immunodominance Of Peptides  Protein antigens are processed to generate multiple peptides; immunodominant peptides are the ones that bind best to the available class I and class II MHC molecules. The illustration shows an extracellular antigen generating a class II–binding peptide, but this also applies to peptides of cytosolic antigens that are presented by class I MHC molecules 27