Somatic recombination at the Ig heavy chain locus

2. * * D  JH rearrangement V  DJH rearrangement Primary RNA transcript Splicing and polyA  mRNA Nascent polypeptide Mature μ heavy chain protein Somatic recombination at the Ig heavy chain locus Germline DNA * Variable Region gene Variable Region exon Gene Segments VH = Variable DH = Diversity JH = Joining JH = Joining ≠ J chain J chain is the “joining chain” for polymeric Ig IgM and IgA

3. The Major Histocompatibility Complex (MHC) Peter Burrows2011 4-6529 peterb@uab.edu • What it is • What it does • Required for antigen recognition by T lymphocytes

4. Learning objectives • To understand: • The differences between how T and B cells recognize antigen • The similarities and differences between MHC class I and class II expression and function • The consequences of MHC polymorphisms

5. Differences in antigen recognition by B and T lymphocytes • T cell antigen receptor • T cell receptor (TCR) • T cells • Transmembrane protein • Transmembrane protein on effector cells • CD4 Helper T Cells • CD8 Cytotoxic T Cells • B cell antigen receptor • Immunoglobulin (Ig) (BCR) • B cells • Transmembrane protein • Secreted by effector cells (Plasma cells)

6. Review of Differences in T and B Cells • B cells • Recognize native protein antigens in solution or on cell surfaces • Secreted antibody is effector molecule • Antibodies can operate at a distance

7. Review of Differences in T and B Cells • B cells • Recognize native protein antigens in solution or on cell surfaces • Secreted antibody is effector molecule • Antibodies can operate at a distance • T cells • Recognize peptides from degraded antigens • Peptides are displayed on cell surfaces in association with specialized proteins (MHC)

8. Antigen-antibody Interaction Heavy Chain Lysozyme Antigenic Determinant Epitope Light Chain

9. Proteases TCR #1 TCR #2 Antigen must be “processed” inside of cells to be recognized by T cells Lysozyme

10. T cells recognize processed (degraded) protein antigens plus MHC TCR 2

11. Phagocytosis Processing of external antigens

12. Processing of internal antigens Death Signal! Viral proteins

13. Review of Differences in T and B Cells • B cells • Recognize native protein antigens in solution or on cell surfaces • Secreted antibody is effector molecule • Antibodies can operate at a distance • T cells • Recognize peptides from degraded antigens • Peptides are displayed on cell surfaces in association with specialized proteins (MHC) • Antigen-specific T cell functions require direct cellcell interactions

14. Major Histocompatibility Complex • Discovered using inbred strains of mice and examining tumor immunity

15. Normal skin rejected Tumor rejected!

16. Major Histocompatibility Complex - MHC • Discovered using inbred strains of mice and examining tumor immunity • Were really studying transplantation immunology – histocompatibility antigens • MHC is the major histocompatibility antigen that needs to be matched for organ transplantation • A complex of linked genes encodes the MHC proteins • Normal function of MHC is to display peptide antigens (self AND non-self) to T cells

17. MHC • MHC I and MHC II • Expression and function • Structure • Genes and polymorphisms • MHC and T cell responses

18. MHC Class I • Protein expressed on all nucleated cells • Presents peptide to CD8 T cells • Cytotoxic “killer” cells • Kill virus infected cells Virus infected cell Tc killing virus infected cells

19. MHC Class II • Expressed by specialized antigen presenting cells (APC) • Dendritic cells • B cells • Macrophages • Presents peptide to CD4 T cells • “Helper” T cells • Help B cells proliferate, differentiate, isotype switch • Help activate macrophages to kill intracellular pathogens

20. CD4 T cell helping a B cell

21. B Cell #1 Class I Class II Selfpeptide Foreign peptide BCR

22. CD4 T Cell B Cell #2 B Cell #1 TCR Class I Class II Selfpeptide Foreign peptide

24. MHC Structure Class I Class II

25. Class I and Class II MHC Molecules • Membrane bound glycoproteins • Structurally very similar • Both have 4 domains • 2 membrane proximal domains • 2 membrane distal domains that form a peptide binding cleft

26. 3-D Structure of Human Class I HLA Molecule

27. Peptide

28. Peptides in the MHC groove

30. CD8 T Cell Virus infected cell

31. CD4 T Cell Antigen Presenting Cell (APC)

32. The human MHC gene complexHLA – human leukocyte antigen

33. Different MHC can bind different peptides

34. MHC Polymorphisms • Allelic variations in MHC genes • Concentrated in the peptide binding regions of Class I and Class II

35. MHC Polymorphisms

36. MHC Polymorphisms • Allelic variations in MHC genes • Concentrated in the peptide binding regions of Class I and Class II • Population level • In an individual, all DP are identical, all B are identical, etc. No gene rearrangements with the MHC!

37. Consequences of MHC Polymorphism • Organ and tissue transplants are difficult • Polymorphic residues change the peptide binding specificity of the MHC • If all MHC were identical, pathogens might avoid immune detection by mutation to prevent MHC binding

38. Tc Tc Why have two antigen recognition systems?

39. Novosibirsk Airport 2/06