CHAPTER 6 Major Histocompatibility Complex MHC Molecules and

CHAPTER 6 Major Histocompatibility Complex (MHC) Molecules and Antigen Presentation to T Lymphocytes

Principal functions of T lymphocytes are defense against intracellular microbes and activation of other cells, such as macrophages and B lymphocytes. All these functions require that T lymphocytes interact with these cells.

B cell activation T cell antigen receptors have evolved to see antigens derived from antigens that are inside cells and are displayed by cell surface molecules. This is in striking contrast to B lymphocytes, whose antigen receptors and secreted products, antibodies, can recognize antigens on microbial and host cell surfaces, and soluble cell-free antigens.

Features of Major Histocompatibility Complex-Dependent Antigen Recognition by T Lymphocytes

ü The Antigen receptors of CD 4+ and CD 8+ T cells are specific for peptide antigens that are displayed by Major Histocompatibility Complex (MHC) molecules. ü The function of MHC molecules is to bind and display peptides for recognition by CD 4+ and CD 8+ T cells. üMHC recognition is also required for the maturation of these T cells, ensuring that mature T cells are restricted to recognizing only MHC molecules with bound antigens. üMHC molecules can bind and display peptides and no other types of molecules, and this is why CD 4+ and CD 8+ T cells recognize peptides. üMHC molecules are highly polymorphic, and variations in MHC molecules among individuals.

v There are two main types of MHC gene products, called class I MHC (present peptides to CD 8+ CTLs) molecules and class II MHC (present to CD 4+ helper T cells) molecules. v Antigen-presenting cells display peptide-MHC complexes for recognition by T cells and also provide additional stimuli that are required for the full responses of the T cells. v Different cell types function as antigen -presenting cells to activate naive T cells or previously differentiated effector T cells

Functions of different antigen-presenting cells ü DCs are the most effective APCs for activating naive T cells and therefore for initiating T cell responses. ü Macrophages and B lymphocytes also function as APCs, but mostly for previously activated T cells rather than for naive T cells.

Properties and Functions of Antigen-Presenting Cells üDCs, macrophages, and B lymphocytes express class II MHC molecules and other molecules involved in stimulating T cells. üThese three cell types have been called professional APCs. üAll nucleated cells can present peptides to CD 8+ CTLs.

Routes of Antigen Entry The common routes through which foreign antigens, such as microbes, enter a host are the skin and the epithelia of the gastrointestinal and respiratory systems. Dendritic cells are the cells that are best able to capture, transport, and present antigens to T cells. Classical DCs are present in most epithelia that interface with the external environment and are enriched in lymphoid organs.

Role of dendritic cells in antigen capture and presentation v The DCs are activated by signals (innate pattern recognition receptors) and by cytokines, such as tumor necrosis factor (TNF), produced in response to the microbes. v By Activation the immature or resting DCs converts to mature cells that are able to present antigens to naive T cells and to activate the lymphocytes.

Several properties of DCs make them the most efficient APCs for initiating primary T cell responses: ü 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. ü DCs express receptors that enable them to capture and respond to microbes. ü DCs migrate from epithelia and tissues via lymphatics, preferentially into the T cell zones of lymph nodes. ü Mature DCs express high levels of peptide-MHC complexes, costimulators, and cytokines, all of which are needed to activate naive T lymphocytes.

THE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) Discovery of the Human MHC

v The MHC was discovered from studies of tissue transplantation in mice. v Tissues, such as skin, exchanged between nonidentical individuals are rejected. v The genetic region that controlled graft rejection and contained several linked genes was named the Major Histocompatibility Complex (MHC). v In mice this region was named histocompatibility-2, or simply H-2. v The Human MHC was called human leukocyte antigens (HLA). v The proteins encoded in the mouse H-2 locus and the HLA proteins identified in humans had very similar basic structures. v In the 1960 s and 1970 s, it was discovered that MHC genes are of fundamental importance for all immune responses to protein antigens, the relevant genes were called immune response (Ir) genes. v It is cleared that Ir genes are, in fact, MHC genes that encode MHC molecules that differ in their ability to bind and display peptides derived from various protein antigens.

MHC Restriction: T cell can interact with both the self-major histocompatibility complex molecule and the foreign peptide that is bound to it, but will recognize and respond to the antigen, only when it is bound to a particular MHC molecule. ü 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.

MHC Genes

MHC Genes v Polymorphism refers to variations in a gene among individuals in a population. An allele is a variant form of a given gene. v The MHC locus contains two types of polymorphic MHC genes, the class I and class II MHC genes, which encode two groups of structurally distinct but homologous proteins, and other nonpolymorphic genes whose products are involved in antigen presentation. v Class I and class II MHC genes are the most polymorphic genes present in any mammalian genome. v In the population, the total number of HLA alleles with different amino acid sequences is estimated to be over 10, 000. v MHC genes are codominantly expressed in each individual.

Short arm of chromosome 6 Chromosome 17 In human: Ø Class I MHC genes: HLA-A, HLA-B, and HLA-C. Ø Class II MHC genes: HLA-DP, HLADQ, and HLA-DR. In mouse: Ø Class I MHC genes: H-2 K, H-2 D, and H-2 L Ø Class II MHC genes: I-A and I-E

Expression of MHC Molecules v The set of MHC alleles present on each chromosome is called an MHC haplotype. For instance, an HLA haplotype of an individual could be HLA-A 2, B 5, DR 3. v All heterozygous individuals have two HLA haplotypes. v Class I molecules are expressed on virtually all nucleated cells, whereas class II molecules are expressed only on dendritic cells, B lymphocytes, macrophages, thymic epithelial cells, and a few other cell types. v This pattern of MHC expression is linked to the functions of class I– restricted CD 8+ and class II–restricted CD 4+ T cells.

Enhancement of class II MHC molecule expression The expression of MHC molecules is increased by cytokines produced during both innate and adaptive immune responses

Structure of Class I MHC Molecules Binding site of CD 8 ü Class I molecules are composed of a polymorphic α chain noncovalently attached to the nonpolymorphic β 2 -microglobulin (β 2 m). ü The polymorphic residues, which are the amino acids that vary among different MHC alleles, are located in the floor and walls of this cleft.

Structure of Class I MHC Molecules Binding site of CD 4 ü Class II molecules are composed of a polymorphic α chain noncovalently attached to a polymorphic β chain. ü The polymorphic residues are located in the α 1 and β 1 segments, in and around the peptidebinding cleft, as in class I MHC molecules.

Features of Class I and Class II MHC Molecules ü Most individuals are heterozygous for MHC genes and therefore express six different class I molecules on every cell, containing α chains encoded by the two inherited alleles of HLA-A, B, and C genes. ü Each heterozygous individual expresses six to eight pairs of class II MHC α and β chain molecules, one set each of DP and DQ, and one or two of DR.

Peptide-MHC complex v MHC molecules show a broad specificity for peptide binding, in contrast to the fine specificity of antigen recognition by the antigen receptors of lymphocytes. Very small numbers of peptide-MHC complexes are capable of activating specific T lymphocytes. v The peptides that bind to MHC molecules share structural features that promote this interaction. One of these features is the size of the peptide. v In addition, peptides that bind to a particular MHC molecule contain amino acid residues that allow complementary interactions between the peptide and that MHC molecule.

PROCESSING OF PROTEIN ANTIGENS v. Antigen processing: convert protein antigens present in the cytosol or internalized from the extracellular environment into peptides and load these peptides onto MHC molecules for display to T lymphocytes.

The class I MHC pathway of antigen presentation Proteasomes are large multiprotein enzyme complexes with a broad range of proteolytic activity that are found in the cytoplasm and nuclei of most cells.

The class II MHC pathway of antigen presentation Enzyme-containing vesicles secondary lysosome (protease) Proteins : extracellular proteins, cell surface proteins, and intracellular proteins that are routinely included in autophagosomes during the process of autophagy.

The functions of class II MHC–associated invariant chain and HLA-DM

Comparative Features of Class I and Class II MHC Pathways of Antigen Processing and Presentation

Cross-presentation of antigens to CD 8+ T cells v Tumor cells or infected cell 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 CD 8+ T cells.

Presentation of extracellular and cytosolic antigens to different subsets of T cells

Immunodominance of peptides Immunodominant peptides are the ones that bind best to the available class I and class II MHC molecules and the majority of the responding T cells are specific for them.

PRESENTATION OF NONPROTEIN ANTIGENS TO SUBSETS OF T CELLS q The best defined of these populations are NKT cells and γδ T cells q NKT cells express markers that are characteristic of both natural killer (NK) cells and T lymphocytes and express αβ T cell receptors with very limited diversity. q NKT cells recognize lipids and glycolipids displayed by the class I– like nonclassical MHC molecule called CD 1. q γδ T cells recognize many different types of antigens, including some proteins and lipids, as well as small phosphorylated molecules and alkyl amines.