Rendon MHC presentation, A Brief Introduction.
- 1. Major Histocompatibility Complex Johnathan Rendon Advanced Cell Biology 12-05-17
- 2. What is the Major Histocompatibility Complex? Cluster of genes found in all mammals Play a role in discriminating self from non-self via antigen presenting structures The MHC was discovered via inbred mice strains MHC genes are called Immune response genes
- 3. Structure = Polymorphic glycoprotein 3 main classes. MHC I, MHC II, MHC III MHC I and MHC II most well known MHC II is Promiscuous- Cleft allows for the entry of more than just one specific peptide sequence. Polymorphic proteins ( recognize several different Ags ) Minor Histocompatibility Complex also plays essential immune response roles.
- 4. MHC I vs. MHC II Class I is more closed Class II is more open Class1 Length conserved (8-10 amino acids) Can bulge (gives Flexibility) Generally hydrophobic Class 2 Length not generally conserved 13-18 amino acids Opens wider
- 5. MHC is codominantly expressed How are haplotypes inherited? One haplotype from mom and the other from dad They’re presented differently Different peptides are recognized Self MHC Restricted Polygenism
- 6. Inherited has haplotypes (Combination of alleles in a chromosome) More than one type of MHC molecule in each individual Extensive differences in MHC molecules between individuals Haplotype influences the immune response Polymorphic proteins and Polygenic Advantageous? Genes in the MHC are tightly LINKED and usually inherited in a unit well known as an MHC HAPLOTYPE
- 7. MHC allele A MHC allele B Polymorphism and MHC: Net Result: Ag binding specificity difference Changes in the pockets, walls and floor of the peptide binding cleft alter types of peptide able to bind MHC Products of different MHC alleles bind a different repertoire of peptides P S AYS I K I R G Y YV Q Q L MHC allele A MHC allele B Polymorphic nucleotides encode amino acids associated with the peptide binding site
- 8. Cell MHC production & processing Antigen processing is important because It can provide clues about what is going on inside of the cell Antigen of extracellular origin= Exogenous Pathway= MHC II • Antigen taken in, digested by enzymes, and fused with a vesicle containing MHC II Intracellular origin=Endogenous pathway= MHC I Lysed Ag transported into RER by TAP transporter • Antigen detected within cell and is cleaved, processed, and exocytosed to be presented on membrane on MHC I
- 9. Function (MHC Class I) MHC I is in virtually all nucleated somatic cells, pAPCs, NK, NKT, and CD8+ T cells Self-MHC restriction: T cells respond to only cells expressing MHC I of the same haplotype The restriction is between having the same haplotype and The same TCR
- 10. Function (MHC Class II) Self-MHC restriction: CD4+ T cells respond to only cells expressing MHC II of the same haplotype CD4+ Helper T cell rely on MHC II for the peptides ability to bind to a target antigen. MHC II is present on cells known as antigen presenting cells (APCs) such as macrophages, DCs, eosinophils, and B cells (B cell pathway shown on right). Ultimately, signaling leads to gene activation for specific immunological effects depending on the transcription factor.
- 11. Antigen Recognition: • MHC must recognize the enormous diversity of Antigens Antigen are extremely diverse Adaptive Immune system must not just recognize antigens but also remember
- 12. Professional Antigen Presenting Cells (pAPCs)
- 13. Transplant rejection occurs as a result of foreign MHC immune responses A x B Mom and Dad A B X A x B ACCEPTED REJECTED A B (A x B) mice antigens recognised as foreign by parental strains. Why? (A x B) mice antigens accepted. Why? Allograft (Transplant between genetically different same species Allo-antigen Histocompatible NO Immune response Histoincompatible Immune response
- 14. Production of CD4+ and CD8+ cells Fit for the Job? • Immature T cells: • positive selection followed by negative selection • During selection changes in the membrane markers occur • Selection process involve highly specific challenges • If they fail the test, they die • Importance: Auto-immunity prevented
- 15. Possible treatment of invasive MAGE-A3 Receptor Specific MHC Class II–Restricted T-Cell Cancer GMO T CELLs J Clin Oncol 35:3322-3329. © 2017 by American Society of Clinical Oncology
- 16. “Most current strategies use genes that encode major histocompatibility complex (MHC) class I–restricted T-cell receptors (TCRs) or chimeric antigen receptors to genetically modify CD8+ T cells or bulk T cells for treatment.). “ (p. 3322 Yong-Chen Lu et. Al.) Use of not only MHC restricted but ALSO Ag restricted Specifically, MHC class II–restricted and HLA-DPB1*0401–restricted GMO CD4 cells may help aid the battle with cancer TCR that recog- nized the cancer germline antigen, MAGE-A3 (melanoma-associated antigen-A3
- 17. Eosinophils, More Than Just Allergy/Inflammation Causing Cells Cancer Immunol Res 2014;2:1-8.
- 18. References and photo credits Owen, Judy (2013-01-25). Immunology. W. H. Freeman. Kindle Edition. J Clin Oncol 35:3322-3329. © 2017 by American Society of Clinical Oncology J Bacteriol. 2016 Jan 19;198(7):1013-21. doi: 10.1128/JB.00823-15 https://cdn.zmescience.com/wp-content/uploads/2014/09/cell_artificial_kinetic.gif https://i.makeagif.com/media/5-10-2015/BOgBZ7.gif giphy.com http://www.cellsystems.org/images/DCturn2new.gif Cancer Immunol Res 2014;2:1-8.
Editor's Notes
- #4: Each recognize several different antigens (Ags) not just a specific single Ag MHC 1-8-10 aa MHC 2 13-18 aa, more open •
- #6: Two of each of the six types of MHC molecule are expressed Yet, MHC alleles are NOT randomly distributed in the population Alleles segregation based on lineage and race Genes in the MHC are tightly LINKED and usually inherited in a unit called an MHC HAPLOTYPE
- #7: alleles designated by small letter superscripts Polymorphism and polygenism in the MHC protects the population from pathogens evading the immune system A completely heterozygous mouse would have 8 different MHC 2 and 6 different MHC 1 Each human usually expresses: 3 types of MHC class I (A, B, C) and 3 types of MHC class II (DR, DP,DQ) to prevent evasion by pathogens
- #9: Class 1:. Ag’s detected within the cell itself. Cytosol RER. Ag targeted and marked via UbQ and then processed by immunoproteosome. Go make it to the RER, TAP ( a ATP binding casesete). The Ag is folded by chaperones so it can fit the MHC (1) and Class 2: Ags taken in by endocytic clathrin coated vesicles. The vesicle meets a vesicle containing MHC 2 protein with its binding site protected by CLIP and Ag replaces clip. MO and DCs process via both MHCI and MHC II Invariant chain held by actin and myosin
- #10: MHC 1: By almost all nucleated cells, like NKs which kill when MHC1(lo/-) T cells: restricted to self MHC haplotypes and self Ag Importance: This interaction leads to cell proliferation to respond to a foreign invader. The activated T cell makes many copies of itself with that particular Ag and proceed to kill the Invaders expressing the peptide presented.
- #11: MHC 2 is (normally) a characteristic of APCs Acticated Mos
- #12: bind to peptide antigens
- #13: exogenous antigens in certain cell types (mainly DCs) can gain access to class I presentation pathways in a process called cross-presentation.
- #14: F1 hybrid (one set of alleles from each parent) Mice of strain (A x B) are immunologically tolerant to A or B skin inflammation and lymphocyte infiltration Transplant rejection is due to an antigen-specific immune response with immunological memory. Factors influencing rejection Class 2 more important than class 1 because indirect presentation Self MHC binds TCR to foreign MHC stronglyBecomes activated, activates a lot of T cells (Direct allo-activation)
- #15: Double positive cell Positive Selection of cells responsive to MHC Double positive cell; Negative Selection of cells responsive to MHC Single-positive cell; CD4+ Single-positive cell; CD8+
- #18: \