Course no and title: VPATH 603,Immunopathology.Name: Md. Fayezur Rahaman.

Roll No:16VPATHJJ04MReg No: 37164

Department of PathologyBangladesh Agricultural University, Mymensingh

MHC CLASS I MOLECULES

MHC molecules

Major Histocompatibility Complex Cluster of genes found in all mammals Participant in both humoral and cell-mediated immunity Act as antigen presenting structures Polymorphic glycoproteins

MHC class I ?

MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules (the other being MHC class II) and are found on the cell surface of all nucleated cells .

Aspects of MHC

1. MHC molecules are membrane-bound. Recognition by T cells requires cell-cell contact.

2. Peptide from cytosol associates with class I MHC and is recognized by Tc cells.

3. Although there is a high degree of polymorphism for a species, an individual has maximum of six different class I MHC products.

4. A peptide must associate with a given MHC of that individual, otherwise no immune response can occur. That is first level of control. Mature T cells must have a T cell receptor that recognizes the peptide associated with MHC. This is the second level of control.

Functions

• Their function is to display peptide fragments of non-self proteins from within the cell to cytotoxic T cells;

• This will trigger an immediate response from the immune system against a particular non-self antigen displayed with the help of an MHC class I protein.

1

3

2

MHC-encoded -chain of 43kDa ,Made Up Of 3 Domains (1, 2 and 3)

Overall structure of MHC class I molecules

2m 2-microglobulin, 12kDa, non-MHC encoded, non-transmembrane, non covalently bound to 3 domainThe a3 segment of the MHC I , is highly conserved among MHC1 & serves as a binding site for CD8

Peptide antigen in a groove formed from a pair of a-helicies on a floor of anti-parallel b strands

-chain anchored to the cell membrane

Antigen Processing and Presentation

Antigen processing

• Conversion of native antigen (large globular protein) into peptides capable of binding to MHC molecules

• Occurs in cellular compartments where MHC molecules are synthesized and assembled (ER)– Determines how antigen in different cellular compartments

generates peptides that are displayed by class I or class II MHC molecules

What Does the αβ T Cell Receptor (TCR) Recognize?

1. Only fragments of proteins (peptides) associated with MHC molecules on surface of cells

• Helper T cells CD4+(Th) recognize peptide associated with MHC class II molecules

• Cytotoxic T cells CD8+ (Tcyt) recognize peptide associated with MHC class I molecules.

Antigen-presenting cells

Dendritic cells

Assembly and stabilization of class I MHC molecules

When MHC-I and endogenous antigens are displayed on the plasma membrane, T cells proliferate, producing cytotoxic T cells. Cytotoxic T cells destroy cells displaying the antigens (Cell-mediated response)

Effect of viruses

MHC class I molecules are loaded with peptides, generated from the degradation of cytosolic proteins in proteasomes. As viruses induce cellular expression of viral proteins, some of these products are tagged for degradation, with the resulting peptide fragments entering the endoplasmic reticulum and binding to MHC I molecules. It is in this way, the MHC class I-dependent pathway of antigen presentation, that the virus infected cells signal T-cells that abnormal proteins are being produced as a result of infection.

The fate of the virus-infected cell is almost always induction of apoptosis through cell-mediated immunity , reducing the risk of infecting neighboring cells.

Therefore, in the absence of MHC I molecules, NK cells are activated and recognize the cell as aberrant, suggesting that it may be infected by viruses attempting to evade immune destruction.

Summary

Cellular and Molecular Immunology 8th Ed. (2015) by Abbas et al.

MHC IComposed of an α (or heavy) chain in a non-covalent complex with a β2- microglobulin

Recognized by CD8+ T cellsExpressed on all nucleated cellsCytosolic proteins are proteolytically degraded in the proteasome

References:1. Hewitt, E.W. (2003). "The MHC class I antigen presentation pathway: strategies for viral immune

evasion". Immunology. 110 (2): 163–169. doi:10.1046/j.1365-2567.2003.01738.x. PMC 1783040free to read. PMID 14511229.

2. http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/H/HLA.html#Class_I_Histocompatibility_Molecules Kimball's Biology Pages, Histocompatibility Molecules

3. Syken, J; Grandpre, T; Kanold, P. O.; Shatz, C. J. (2006). "PirB restricts ocular-dominance plasticity in visual cortex". Science. 313 (5794): 1795–800. doi:10.1126/science.1128232. PMID 16917027.

4. Koopmann JO, Albring J, Hüter E, et al. (July 2000). "Export of antigenic peptides from the endoplasmic reticulum intersects with retrograde protein translocation through the Sec61p channel". Immunity. 13 (1): 117–27. doi:10.1016/S1074-7613(00)00013-3. PMID 10933400.

5. Albring J, Koopmann JO, Hämmerling GJ, Momburg F; Koopmann; Hämmerling; Momburg (January 2004). "Retrotranslocation of MHC class I heavy chain from the endoplasmic reticulum to the cytosol is dependent on ATP supply to the ER lumen". Mol. Immunol. 40 (10): 733–41. doi:10.1016/j.molimm.2003.08.008. PMID 14644099.