MHC - Part 1 PDF

Major Histocompatibility Complex (MHC) code for cell surface proteins essential for the adaptive immune It is a tightly systemof genes in linked cluster mammals Their products play roles in intercellular recognition and in discri...

Major Histocompatibility Complex (MHC) code for cell surface proteins essential for the adaptive immune It is a tightly systemof genes in linked cluster mammals Their products play roles in intercellular recognition and in discrimination between self and non-self It participates in the development of both humoral and cell-mediated immune responses T-cells recognize antigen only when it is combined with an MHC molecule MHC molecules act as antigen-presenting structures  MHC (…Cont’d) MHC mediate the interactions of leukocytes with other leukocytes or with body cells It determines donor compatibility for organ transplant It is implicated in the susceptibility to disease and in the development of autoimmunity Particular set of MHC molecules expressed by an individual influences the repertoire of antigens to which that individual’s TH and TC cells can respond It partly determines the response of an individual to antigens of infectious organisms  MHC Genes Humans Mice Present on chromosome 6 Present on chromosome 17 Referred to as the HLA Referred to as the H-2 complex complex Both in humans and mice, the arrangement of genes is different but organized into regions encoding three classes of molecules Encode glycoproteins expressed Present peptide 1)Class I MHC genes on the surface of nearly all antigens to TC nucleated cells cells Encode glycoproteins expressed Present peptide 2)Class II MHC genes on macrophages, dendritic cells antigens to TH & B cells cells Encode secreted proteins having immune functions, 3)Class III MHC genes(components of complement system & molecules  Class I MHC molecules (1st discovered, and are expressed in the widest range of cell types. Expression of Non- classical Class I Non-classical molecules D, E, F is Class II molecules limited to certain Classical – DM & DO specific cell types molecules Classical molecules  Protection of the fetus from being rejected by maternal TC cells Expression of the non-classical class I HLA-G molecules on cytotrophoblasts at the fetal- maternal interface Allelic Forms of MHC Genes Many alleles exist at each locus MHC genes are polymorphic Human MHC loci are closely Crossover linked occurs only Recombination frequency within the H-2 complex is only 0.5% once in every 200 mitotic Eachcycles set of alleles is referred to as a haplotype 1 haplotyp e from mother and 1 haplotyp e from Codomina father nt  Neither of the inbred parental strains can accept a graft from the F1 mice Expresses the MHC proteins of both parental strains on its cells A new haplotype (R) arises from recombination of maternal Histocompatible with both strains haplotypes and able to accept grafts from either parental strain Rare – Identical sets of HLA genes in any two unrelated  Class I and class II MHC molecules are membrane-bound Class glycoproteins. III MHC molecules are a group of unrelated proteins that do not share structural similarity & common function with class I & II molecules.  Exon/Intron Arrangement of Class I and II Genes MHC molecules assemble within the cell During assembly they associate with MHC I 1) Short peptide fragments derived either from proteins being made by the cell MHC 2) Proteins that have been internalized by the II cell through phagocytosis or pinocytosis  Characteristics of Peptide-MHC Molecule 1) MHC molecules show aInteractions broad specificity for peptide binding Single MHC allele (e.g., HLA-A2) can present any one of many different peptides to T cells However, a single T cell will recognize only one of these many possible HLA-A2/peptide complexes 2) Each class I or class II MHC molecule has a single peptide-binding cleft that binds one peptide at a time, but each MHC molecule can bind many different peptides Each individual contains only a few different MHC molecules (6 class I and about 8 or more class II molecules in a heterozygous individual) 3) Peptides that bind to MHC molecules share structural features that promote this interaction Size of the peptide Peptides that bind to a particular MHC molecule contain amino acid residues that allow complementary interactions between the  Characteristics of Peptide-MHC Molecule Interactions 5) Association of peptides and MHC molecules is a saturable interaction with a very slow off-rate To maximize the chance that a particular T cell will find the peptide it can recognize and initiate a response 6) Very small numbers of peptide-MHC complexes are capable of activating specific T lymphocytes APCs continuously present peptides derived from all the proteins they encounter Only a very small fraction of cell surface peptide–MHC complexes will contain the same peptide As few as 100 complexes of a particular peptide with a class II MHC molecule on the surface of an APC can initiate a specific T cell response This represents less than 0.1% of the total number of class II molecules likely to be present on the surface of the APC 7) MHC molecules of an individual can bind and display self & non-  Structural Basis of Peptide Binding to MHC Binding of peptides to Molecules MHC molecules is a noncovalent interaction mediated by residues both in the peptides and in the clefts of the MHC molecules Electrostatic interactions (salt bridges), hydrogen bonding, or van der Waals interactions Peptides bind to the clefts of MHC molecules in an extended conformation Once bound, the peptides and their associated water molecules fill the clefts, making extensive contacts with the amino acid residues that form the β strands of the floor and the α helices of the walls of the  Structural Basis of Peptide Binding to MHC MHC class I molecules – Molecules Longer peptides bulge in the middle, whereas shorter peptides are more extended Contact with the MHC molecule is by hydrogen bonds to anchor residues 1/2 and 8/9 Allows greater variability Residues in the other recognized by specific residues of the peptide T cells β strands in the floor of the cleft contain pockets where residues of peptides bind. Hydrophobic pocket that recognizes hydrophobic amino acids—val, ile, leu, or met—at the C-terminalMost end MHCof the peptide. Pocket allows binding of aI basic residue class (lys or arg) at the C terminus Some of theMHC peptide class I  Structural Basis of Peptide Binding to MHC MHC class II molecules – Molecules Specific interactions of peptides with the α-helical sides of the MHC cleft also contribute to peptide binding by forming hydrogen bonds or charge interactions Since they bind longer peptides, those extend at either end beyond the floor of the cleft MHC genes – As immune response genes; only individuals whose MHC molecules can bind a particular peptide and display it to T cells can respond to Tthat cell peptide receptors recognize both the antigenic peptide and the MHC molecules Peptide defines the fine specificity of antigen recognition MHC residues account for the MHC restriction of the T cells Peptide Binding by MHC I & II Molecules Class I binding requires that There is no such the peptide contain specific requirement for amino acid residues near the class II peptide THANK YOU…!