Major Histocompatibility Complex (MHC)

1. 4/9/2020Department of Life Science, SPU Balaghat1

2. MAJOR HISTOCOMPATIBILITY COMPLEX STRUCTURE AND FUNCTION OF:- •MHC CLASS I MOLECULE •MHC CLASS II MOLECULE •MHC CLASS III MOLECULE DIFFERENCES BETWEEN MHC CLASS I AND II MOLECULES H-2 COMPLEX OF MOUSE MHC COMPLEX OF HUMAN STRUCTURE OF TCR ANTIGEN RECOGNITION BY T CELL MHC I / TC CELL INTERACTION MHC II / TH CELL INTRACTION MHC RESTRICTION ANTIGEN PROCESSING AND PRESENTATION PATHWAYS • THE CYTOSOLIC PATHWAY • THE ENDOCYTIC PATHWAY FUNCTIONS OF MHC 4/9/2020 Department of Life Science, SPU Balaghat 2

4.  MOLECULAR WEIGHT-45 KD.  Class I MHC molecules is a membrane spanning molecule ,approximately 350 amino acids in length, 75 amino acids comprising the transmembrane and cytoplasmic portions. The remaining 270 amino acids are divided into three globular domains α-1,α-2 and α-3.  The alpha chain is a transmembrane glycoprotein encoded by A,B, and C regions of the human HLA complex and within the K and D regions of mouse H-2 complex.  The second portion of the molecule is a small globular protein called β-2 Microglobulin associates with the α-3 domain and is necessary for MHC stability.β-2 Microglobulin is a protein encoded by highly conserved gene located on different chromosomes. 4/9/2020Department of Life Science, SPU Balaghat4

5.  The β2 – microglobulin is non-covalently associated with the α3 domain.  The α1 and α2 domains interact to form 8 antiparallel β strands spanned by 2 long α–helical regions. This region is capable of binding (via non-covalent interactions) a small peptide of about 10 amino acids. This small peptide is "presented" to a T-cell and defines the antigen "epitope" that the T-cell recognizes.  The peptide-binding cleft is located on the top surface of the MHC Class I molecule and it is large enough to bind a peptide of 8 to 10 amino acids. 4/9/2020 Department of Life Science, SPU Balaghat 5

6. 4/9/2020 Department of Life Science, SPU Balaghat 6

8. CLASS II MHC MOLECULE Class II molecules are composed of two polypeptide chains These polypeptides (alpha and beta) are about 230 and 240 amino acids long, respectively, and are glycosylated, giving molecular weights of about 33 kDa and 28 kDa. These polypeptides fold into two separate domains; alpha-1 and alpha-2 for the alpha polypeptide, and beta-1 and beta-2 for the beta polypeptide. 4/9/2020 Department of Life Science, SPU Balaghat 8

9. Between the alpha-1 and beta-1 domains lies a region very similar to that seen on the class I molecule. This region, bounded by a beta-pleated sheet on the bottom and two alpha helices on the sides, is capable of binding (via non-covalent interactions) a small peptide of about 10 amino acids. This small peptide is "presented" to a T-cell and defines the antigen "epitope" that the T-cell recognizes. 4/9/2020 Department of Life Science, SPU Balaghat 9

10. These are heterogenous molecules . Include complement component C2, C4 and factor B(components responsible for formation of C3 convertase). They also include heat shock proteins and tumour necrosis factor. 4/9/2020 Department of Life Science, SPU Balaghat 10

11. MHC class I MHC class II Comprised of an MHC-encoded a chain and a b2-microglobulin chain Comprised of MHC-encoded a and b chains Present on most cells Present only on antigen-presenting cells Bind endogenous antigens synthesized in a cell Binds exogenous antigens Present antigen to cytotoxic T cell lymphocytes Present antigen to helper T cell lymphocytes Bind CD8 adhesion molecules on cytotoxic T cells Bind CD4 adhesion molecules on helper T cells Presence of foreign or over-abundant antigens targets cell for destruction Presence of foreign antigens induces antibody production, and attracts immune cells to area of infection 4/9/2020 Department of Life Science, SPU Balaghat 11

12. The mouse MHC is located on chromosome 17. Class I MHC: • It consists of two major loci, K and D. •These 2 loci are not together but they are separated by class II and class III genes. Class II MHC: •The class II gene complex contains two loci, A and E each of which code for one α- and one ß- chain polypeptide, which form one class II molecule. •The mouse class II gene complex is also known as the I-region and the genes in this complex are referred to as Ir (immune response) genes . •Products of A and E loci are also termed IA and IE antigens, collectively known as Ia antigens. 4/9/2020 Department of Life Science, SPU Balaghat12

13. The human MHC is located on chromosome 6. Class I MHC: •The class I gene complex contains three major loci as B, C and A . • Each these loci codes for a polypeptide, α-chain. •Each α-chain associates with a β-2 microglobulin molecule , This α-β-chain complex is expressed on the cell surface. Class II MHC: •The class II gene complex contains three loci, DP, DQ and DR; each of these loci codes for one α- and a variable number of ß-chain polypeptides which associate together to form the class II antigens. 4/9/2020 Department of Life Science, SPU Balaghat 13

14. It’s a hetrodimer. 2 polypeptide chains are present(α and β) Divided into constant and variable arm. 3 hypervarible regions are present in variable arm for antigen recognition. Assessory molecule called CD3 then transmits the signal. T-cells activation Release of lymphokines. 4/9/2020 Department of Life Science, SPU Balaghat 14

16.  The TCR provides the specificity for an individual T-cell to recognize its particular antigen. However, this recognition is "MHC-restricted" because the TCR also requires interactions with MHC.  Interactions between the CD4 molecule (found on helper T-cells) and class II MHC or the CD8 molecule (found on cytotoxic T- cells) and class I MHC stabilize and consummate the antigen recognition process, allowing helper T-cells to respond to "exogenous" antigens (leading to B-cell activation and the production of antibody) or cytotoxic T-cells to respond to "endogenous" antigens (leading to target cell destruction). 4/9/2020 Department of Life Science, SPU Balaghat16

17. Most Tc cells (CD8+ Cells) possess both T-Cell Receptors (TCR) and CD8+ molecules on their surfaces. These TCRs are able to recognize peptides,only when they are expressed in complexes with MHC I molecules. Due to Genetic recombination events, each T-Cell expresses a unique TCR, which will only bind a specific MHC-Peptide complex. T-Cells that recognize self-peptides are released in the Thymus. Any cell which is hosting a Virus or manufacturing mutant proteins (as in the case of Cancer) will present these foreign Peptides upon its surface. A CD8+ Cell will recognize them and eventually the cell will be destroyed. 4/9/2020 Department of Life Science, SPU Balaghat 17

18. The Helper T-Cells is responsible for regulating almost every Acquired Immune System activity. Helper T-Cells interact with MHC II-Peptide complex, in order to be activated. Instead of CD8 molecule Helper T-Cells, have a molecule called CD4, which binds to MHC II. As in the case of CD8+ Cells, self-reactive cells are destroyed in the Thymus, so if a Peptide is recognized, it is probably of foreign origin. Assuming the APC which presented the MHC II-Peptide complex produce cytokines to allow its own maturation and propagation. These CD4+ Cells will then proceed to supply the necessary cytokines for Immune Responses against antigen they recognize. 4/9/2020 Department of Life Science, SPU Balaghat 18

21. MHC restriction is the recognition of foreign antigen located on the surface of cells. Cytotoxic T lymphocytes usually respond to foreign antigen in association with Class I MHC antigen whereas T helper cells responds to foreign antigen in association with Class II MHC antigens. The presentation of antigens by macrophages to T cells appear to be very specific. The macrophages that present antigen to TH cells should have Class II MHC antigens on their surface whereas macrophages that present antigen to Tc cells should have Class I MHC antigens. When the macrophage bears a different MHC antigen, it cannot cooperate and thus antigen presentation cannot occur, this is called as MHC restriction. 4/9/2020 Department of Life Science, SPU Balaghat 21

22. The intracellular and extracellular antigens are eliminated by different pathways in immune system. There are basically two pathways for their eliminations:- THE CYTOSOLIC PATHWAY:- Generally endogenous antigens are processed in the cytosolic pathway and presented on the membrane with class I MHC molecules THE ENDOCYTIC PATHWAY:- Exogenous antigens are processed in the endocytic pathway and presented on the membrane with class II MHC molecule 4/9/2020 Department of Life Science, SPU Balaghat 22

23. Endogenous antigen are degraded by proteosomes. Peptide is transported to RER via TAP. Class I MHC α chain binds calnexin,then β-2 microglobulin.calreticulam,tapasin and ERP57 bind. MHC capture peptides and chaperones dissociates. Class I MHC-peptide is transported from RER to Golgi complex to plasma membrane. 4/9/2020 Department of Life Science, SPU Balaghat 23

26.  Class II MHC α and β binds invariant chain blocking binding of endogenous antigen.  MHC complex is routed through Golgi to endocytic pathway compartments.  Invariant chain is degraded,leaving CLIP fragment.  Exogenous antigen is taken up,degraded, routed to endocytic pathway compartments.  HLA-DM mediates exchange of CLIP for antigenic peptide.  Class II MHC-peptide is then transported to plasma membrane. 4/9/2020 Department of Life Science, SPU Balaghat 26

28.  Production of Human Leucocyte Antigen Production of Immune Associated Antigens Controls the levels of the Complement Components HLA Complex help In T-cell recognition Graft Rejection Non-immunological function of MHC 4/9/2020 Department of Life Science, SPU Balaghat 28

29. KUBY IMMUNOLOGY- BY OSBARNE,GOLDSBY AND KINDT IMMUNOLOGY- BY ROITT IMMUNOLOGY-BY VED PATHAK 4/9/2020 Department of Life Science, SPU Balaghat 29

Major Histocompatibility Complex (MHC)

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