26. How are peptides derived from proteins in the cytosol able to bind to MHC cl

Question

26. How are peptides derived from proteins in the cytosol able to bind to MHC class I molecules for delivery to the cell surface? 27. What is the role of TAP1/2 in antigen processing and presentation? 28. What are the proteins involved in the loading complex system during MHC class I processing and presentation? 29. Many viruses produce immunoevasins that interfere with antigen presentation by MHC class I molecules. Explain how does Herpes simplex virus affect the antigen presentation process? 30. How are peptides by MHC class II molecules generated? 31. How is the prevention of antigen loading during the assembly of MHC class II in the ER achieved? And why is this prevention process critical? What would be the consequences if this prevention system does not take place? 32. What is the role of HLA-DM during antigen presentation in MHC class II molecules?

Explanation / Answer

26. The peptides derived from the proteins in the cytosol undergo antigen processing and presentation via the endogenous pathway. The ubiquitinylated proteins are degraded by large (20S) immunoproteasomes to produces peptides which get presented via class I- MHC molecules on antigen presenting cells. Peptides get transporterd from cytosol to rough endoplasmic reticulum (RER) by transporter associated with antigen processing (TAP) which translocates the cytosolic peptides into the ER lumen in an ATP-dependent transport mechanism. Here, they get processed to around 9 amino acid containing peptides by ERAP (ER associated aminopeptidases). Chaperones namely, calnexin, calreticulin and tapsin aid in loading of peptide to Class-I MHC molecule (also synthesized in RER).

27. Transporter associated with antigen processing (TAP) is a membrane-spanning transporter protein located in the RER. It is a heterodimer consisting of TAP1 and TAP2 which have multiple transmembrane segments with their cytosolic domains having ATP-binding domain. TAP1 and TAP2 are ATP-binding cassette proteins which enable ATP-dependant transport of peptides in to the RER for antigen presentation. Following ATP hydrolysis, TAP proteins translocate peptides of 8-16 aimno acids and favor peptides with hydrophobic or basic carboxy-acid terminal amino acids.

28. Proteins involved in the loading complex include molecular chaperones namely, calnexin, calreticulin and tapasin. Firstly, Calnexin (resident of ER membrane) gets associated with free class I MHC alpha chain and ERp57 (enzymatic protein) helps in their folding. Following this, the beta2 microglobulin chain binds to the alpha chain to release calnexin. This is followed by association with calreituclin and tapasin (TAP associated- protein) which brings the TAP transporter in proximity with the class I MHC molecule and allows the antigenic peptide to get loaded. Therefore, TAP promotes the peptide capture by class I MHC before being exposed to the luminal environment of RER. Finally, peptide association stabilizes the class I MHC molecule-peptide complex allowing it to be transported to the plasma membrane from RER.

29. HSV inhibits antigen presentation on MHC class I to CD8 T cells by two distinct mechanisms by the viral host shutoff protein (vhs) and the immediate early US12 gene product ICP47. Vhs targets host mRNA for destruction, nonspecifically shutting down antigen presentation at several steps.

Herpes simplex virus (HSV) has a number of genes devoted to immune evasion. One such gene, ICP47, binds to the transporter associated with antigen presentation (TAP) 1/2. ICP47 (immunoevasin) directly targets MHC class I antigen presentation by binding to the transporter associated with antigen presentation (TAP) 1/2 complex, preventing transport of peptides from the cytosol to the endoplasmic reticulum where peptides are loaded into the nascent MHC class I heavy-chain Beta2 microglobulin (Beta2) complex. This prevents the transport of viral peptides into the endoplasmic reticulum, loading of peptides onto nascent major histocompatibility complex (MHC) class I molecules, and presentation of peptides to CD8 T- cells.

30. Class II MHC molecules are generated via the exogenous pathway of antigen processing and presentation. The APCs internalize the antigenic protein via phagocytosis. This is observed in macrophages and dendritic cells which internalize antigens in endocytic vesicles, which moves into different acidic compartments ( early- late endosomes) where it gets framented (by hydrolytic enzymes) different pH conditions) to finally associate generated peptides with class II MHC molecules transported in vesicles from the golgi complex. The antigen is internalized by receptor-mediated endocytosis when membrane-bound antibody recognizes and binds with the antigen to effect this process.

31. The prevention of antigen loading during class II MHC assembly is achieved by the binding of an invariant chain to a newly synthesized class II MHC molecule. This invariant chains prevents premature binding of peptides to the class II molecule and helps to direct the complex from endocytic compartments where it may otherwise bind to different non-specific peptides derived from exogenous antigens. The invariant chain also contains sorting signals in the cytoplasmic tail to direct the transport of class II MHC complex from trans- golgi to andocytic compartments. IF this prevention system does not work properly, the class II MHC molecules may get bound to antigenic peptides destined for class I MHC molecules resulting in false recognition by CD4+ and CD8+ cells. This can result in improper/failure of immune responses where specific responses are required.

32. HLA-DM is a nonclassical class II MHC molecule which is required in the catalysis of exchange of CLIP (class-II associated invariant chain peptide) with antigenic peptides. It is a heterodimer of alpha and beta chains. It associates with the class II MHC alpha chain and functions in removing or editing peptides including CLIP (which transiently associates in the binding groove). The negative regulator of HLA DM, namely, HLA-DO inhibits its role by binding with HLA-DM to prevent its association with CLIP, resulting in the negative regulation of antigen processing.

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