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Specific Defenses of the Host Part 3

Specific Defenses of the Host Part 3. (acquired or adaptive immunity). Mechanisms of the Immune Response, continued. How do MHC class II molecules function?

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Specific Defenses of the Host Part 3

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  1. Specific Defenses of the HostPart 3 (acquired or adaptive immunity)

  2. Mechanisms of the Immune Response, continued • How do MHC class II molecules function? • MHC class II antigens – these molecules bind foreign antigens that have entered the cell via endocytosis. They trigger an immune response by stimulating helper CD4+ T cells. • Both the binding of the T cell receptor to the MHC class II molecule and the peptide as well as the binding of the CD4 molecule to the MHC class II molecule are required for stimulation of the T cell. • The genes that encode MHC Class II molecules are called immune response genes and they determine whether an individual can mount an antibody response to T-dependent antigens.

  3. Presentation of Foreign Antigens Made Outside the Cell to CD4+ T Cells

  4. Presentation of Foreign Antigens Made Outside the Cell to CD4+ T Cells

  5. MHC Class II Interaction with CD4+ T Cells

  6. MHC Class II Interaction with CD4+ T Cells

  7. Mechanisms of the Immune Response, continued • The MHC class II molecules, like the class I molecules, consist of two polypeptide chains called alpha and beta. • Both the alpha and the beta chain are encoded in the MHC class II region. • There are 3 functional loci – DR, DQ, and DP. • Each locus encodes an alpha chain and a beta chain. • In your assay, you will be amplifying a region of the HLA DQ alpha chain.

  8. Human MHC Class II Region

  9. Mechanisms of the Immune Response, continued • Since one inherits (assuming heterozygosity), 6 different loci, and since each locus encodes both an alpha and a beta chain, individuals can express 10-20 different MHC class II molecules/cell. • DR, DQ, and DP beta chains associate mainly with alpha chains from their own family. • The alpha and beta chains can be divided into 4 separate domains or regions: the peptide binding domain, immunoglobulin-like domain, transmembrane domain, and cytoplasmic domain.

  10. The Structure of the MHC Class II Molecule

  11. Mechanisms of the Immune Response, continued • The peptide binding domain • This region is made from alpha 1 and beta 1 with a structure similar to that of class I molecules – an 8-stranded beta sheet plus 2 alpha helices creating a cleft for peptide binding. • In terms of the peptides they bind, since the ends of the cleft are open, bound peptides can extend beyond the cleft. • The peptides that bind to the MHC class II molecules can range in size from 10-30 amino acids.

  12. Mechanisms of the Immune Response, continued • Each MHC class II molecule can bind more than 1 different peptide, but as with the class I molecules, all peptides that bind a single class II molecule will share structural features. • The MHC class II molecules therefore, are said to bind their peptides with loose specificity. • All polymorphic residues are found within the cleft where the peptide binds or where the T cell receptor interacts with the MHC class II molecule. Differences here provide the basis for T cell restriction. • The class II molecules are not as polymorphic as the class I molecules. • In this class you will be amplifying the polymorphic region of the HLA DQ alpha chain.

  13. Polymorphisms within the MHC Class II Molecules

  14. Mechanisms of the Immune Response, continued • The immunoglobulin-like domain • This is the region where the T cell CD4 molecule interacts with the MHC class II molecule (at the beta 2 region). • The transmembrane domain • This domain does not affect the extracellular domain of the molecule. • The cytoplasmic domain • This domain has an unknown function.

  15. Mechanisms of the Immune Response, continued • Intracellular class II molecules have a gamma or invariant chain associated with them to prevent endogenous peptides from binding. • The invariant chain is removed upon the fusion of an endosome with an exocytic vesicle containing an MHC class II molecule. • The exogenous peptides are then loaded onto the MHC class II molecule. • In summary:

  16. The Structure of the MHC Class II Molecule

  17. Presentation of Foreign Antigens Made Outside the Cell to CD4+ T Cells

  18. MHC Class II Interaction with CD4+ T Cells

  19. MHC Class II Interaction with CD4+ T Cells

  20. Mechanisms of the Immune Response, continued • Located between the class I and the class II genes are genes whose expression is necessary for efficient assembly of class I molecules. • This includes the genes that encode the TAP proteins that function in transport of proteins (or peptides) from the cytosol into the ER where they can associate with newly formed class I molecules. • Genes that encode the cytosolic protease complex proteins are also found there as are the genes that encode the complement components.

  21. Presentation of Foreign Antigen Made Within the cell to CD8+ T Cells Which MHC Class is this?

  22. T-independent antigens revisited • What is the hypothesis regarding why T-independent antigens can stimulate B cells without the help of T cells? • Conversely, why can’t T-independent antigens enlist the help of T cells? • Hint: what is required to stimulate a T cell?

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