Antigen Presentation (Part 1 of 2) - BMS 545 Immunology - September 20, 2024

WELCOME! BMS 545 IMMUNOLOG Y SEPTEMBER 20, 2024 ANNOUNCEMENTS  Office Hours  Tuesday- 4-5 pm virtual  Thursday 4-5 pm in- person  No more homework until Module 3!!!!!  OBJECTIVES  Identify & explain antigen processing & presentation (basics- why is it important?)  Differenti...

WELCOME! BMS 545 IMMUNOLOG Y SEPTEMBER 20, 2024 ANNOUNCEMENTS  Office Hours  Tuesday- 4-5 pm virtual  Thursday 4-5 pm in- person  No more homework until Module 3!!!!!  OBJECTIVES  Identify & explain antigen processing & presentation (basics- why is it important?)  Differentiate professional APCs from atypical/amateur APCs, esp. how they present, and what types of antigens. What cell types are they found on?  Identify & explain the locations & functions of MHC molecules  Compare & Contrast MHC I & MHC II molecules including structure, formation, function, type of peptide, cells they present to, etc.  Describe the importance of MHC restriction  Describe the “Sweaty T-Shirt” Study (Your “Also A Scientist”) WHY SHOULD YOU CARE? (“FUN” SCIENCE STUDY) The Sweaty T-Shirt Study https://www.youtube.com/watch?v=qgeZnuevxnA  ANTIGEN PROCESSING, PRESENTATION & RECOGNITION  T cell activation must be tightly regulated- difficult to slow down cell-mediated immune response once started  Immune system has system of checks & balances that prevent T-cells from deciding on their own what antigens to destroy (limits risk of autoimmunity)  Therefore, it is NECESSARY for other cells to process & then present foreign antigens to T cells with additional signals required for recognition & full activation of the cell- mediated response  Antigen processing and presentation 5-5 T-cell receptors recognize peptide antigens bound to MHC molecules peptide (red)+ MHC (yellow) = pMHC Figure 5.8 Antigen processing and presentation antigen:MHC = pMHC  A pathogen & its proteins can be synthesized by an infected human cell or be taken up from extracellular environment  All human cells have housekeeping mechanisms that serve to remove damaged or unwanted proteins  These mechanisms degrade proteins into small peptides & are used to produce the pathogen-derived peptides that are bound by MHC molecules, displayed on cell surface, & presented to T cells TYPES OF ANTIGEN PRESENTING CELLS (APCS) PROFESSIONAL VS. AMATEUR ANTIGEN PRESENTATION MAJOR HISTOCOMPATIBILITY COMPLEXES  Major Histocompatibility Complex (MHC)- membrane bound protein that displays antigen peptides to T-cells  MHC proteins encoded by genes from both parents to increase diversity of MHC molecules  Each MHC gene has multiple alleles (polymorphic) so that each person has unique MHC pattern (except identical twins)  Ability to fight infection varies between people, as every person’s adaptive immune system responds slightly differently to microbes  These genes are found in all mammals, but not in microorganisms. Consequently, the immune system uses these MHC proteins to recognize cells in body as “self"  Human MHC molecule is located on chromosome 6  Class I gene complex contains 3 major loci, B, C & A  Class II gene complex contains at least 3 loci, DP, DQ & DR  Aka human leukocyte antigens (HLA)- important in tissue typing to match transplant organs, etc. The major histocompatibility complex 5-15 Human MHC diversity is the product of gene families & genetic polymorphisms The major histocompatibility complex 5-20 Human populations all maintain a diversity of HLA class I and class II alleles Without diversity of HLA class I & class II allotypes humans would not survive Figure 5.38 MHC heterozygosity delays the progression to AIDS in people infected with HIV-1  Antigen processing and presentation 5-12 All nucleated cells express MHC class I, whereas MHC class II is mainly expressed by professional antigen-presenting cells (APCs) Tissue distribution of MHC molecules → *Activated T cells have cell-surface MHC class II, whereas resting T cells do not † Most cell types in the brain are MHC class II– negative, but microglial cells, which are related to macrophages, are MHC class II–positive.  Antigen processing and presentation  5-7 MHC class I and class II molecules have MHC class similar I- composed of a structures membrane-bound heavy chain (α) & a soluble light chain called β2- microglobulin (β2m)  Heavy chain has 3 extracellular domains, α1 & α2 domains that form peptide-binding groove  α3 domain & β2m are immunoglobulin-like domains with similar structure that interact to support peptide- binding groove (aka α1 & α2)  MHC class II- composed of 2 structurally similar, membrane- bound α & β chains that have an amino-terminal domain resembling the α1 & α2 domains of MHC class I & an immunoglobulin-like domain Figure 5.13 The MHC fold  MHC CLASS I  Co-dominantly expressed 45-kDa MHC class I molecules with β2 microglobulin (β2m) found on surface of ALL NUCLEATED cells  MHC Class I three genetic loci, HLA-A, -B, & -C, are highly polymorphic with more than 100 alleles at each locus  MHC class I molecules (HLA-A, HLA-B, or HLA-C) together with β2 microglobulin (β2m) form a closed peptide cleft between α1 & α2 domains that can noncovalently bind an 8-9 amino-acid peptide  Slight structural variations in the binding cleft (binding groove) of different allelic forms = different peptides may preferentially fit into clefts of some MHC class I molecules better than others  Additional “nonclassical” class I molecules (e.g., those encoded by the HLA-E, -F, -G, -H loci) show limited variability & tissue distribution & may function to present carbohydrate & peptide fragments; CD1d is one of many examples  MHC CLASS II  Normally only expressed on surfaces of APCs, some activated T cells, & some specialized epithelial cells in thymus & intestine  Co-dominantly expressed as noncovalent heterodimers, a 32-38 kDa α chain & a 29-32 kDa β chain form a binding groove (α1 & β1 domains) that can accommodate 18-20 amino acid peptide  Encoded within the HLA-DP, -DQ, & -DR regions with α & β loci (DPα, DPβ, DQα, DQβ, etc.)  After synthesis, MHC class II α & β chains combine only with others encoded within same region (e.g., DPα associates only with DPβ but never with DQβ or DRβ)  Antigen processing and presentation 5-6 Two classes of MHC molecule present peptide antigens to two types of T cell