Immunology: Antigen capture and presentation
CD/MHC relationship
CD8 T cells: MHC I CD4 T cells: MHC II
MHC presentation
Class I are expressed on all nucleated cells, but class II are expressed mainly on dendritic cells, macrophages and B lymphocytes.
MHC restriction
Class II ONLY binds to CD4 Class I ONLY binds to CD8
Class I MHC
Display peptides to CD8+ T cells Expressed on all nucleated cells Structure: composed of α-chain bound to β2- microglobulin (not part of MHC locus)
Class II MHC
Display to CD4+ Helper T cells Expressed primarily on dendritic cells, macrophages, and B cells Structure: composed of α and β chains CD4 helper cells help B lymphocytes to produce antibodies and they help phagocytes to destroy ingested microbes.
Antigens recognized by B Lymphocytes
recognize broad range of macromolecules - proteins, polysaccharides, lipids, nucleic acids - receptors are membrane bound antibodies - antigens present in soluble form or membrane bound
Antigens recognized by T lymphocytes
recognize only peptide fragments - T cell receptor (TCR) - antigens must be presented by MHC molecules on antigen presenting cells (APCs) mhc molecule presents the fragment. t cell comes in and recognizes the certain peptide. not a strong bond; need other components to come in
divisions of the adaptive immune system
Humoral and Cell-mediated
Major MHC Properties
MHC bind peptide in non-specific manner not selective - bind self peptides and microbe peptides equally! key point: mhc binds any peptide that it can bind. then they let the t cell receptor decide if its something to worry about
Superantigen
substance that activates T cells by cross linking T cells and MHC II, thus stimulating large numbers of T cells - trying to activate these things outside of the normal process. - robust immune response. this is how a lot of toxins work. *production of so many cytokines that our body goes into septic shock and shuts down* Bad!
Antigen
substances that can be specifically recognized by the adaptive immune system
Immunogen
subtype of antigen; increase the response from the immune system molecule that induces an adaptive immune response
Follicular Dendritic Cells
the b cell-rich lymphoid follicles of the lymph nodes and spleen contain a population of cells called ___________. Function is to display antigens to activated B cells. display to germinal center b cells and select high-affinity b cells during humoral immune response.
Identify and recognize the role of antigen presenting cells (APC) in the immune response.
the cells that capture microbial antigens and display them for recognition by T lymphocytes. Specialized "professional" APCs have specific functions in adaptive immunity 1. Dendritic cells: Primary APCs that induce T cell maturation; Migrate to lymph nodes to present antigens 2. Macrophages: Presentation of antigen related to activation by T cells 3. B cells; Involved in the development of the humoral immune response
Describe the process by which rare antigen-specific lymphocytes find antigens.
they continuously circulate between the lymph and blood until they encounter their antigen. In a lymph node, for example, lymphocytes continually leave the bloodstream by squeezing out between specialized endothelial cells lining small veins called postcapillary venules.
Naive T activation
a naive T cell is a mature cell, but needs activation by an APC. Naive T need to see protein and antigens presented by dendritic cells to initiate clonal expansion and differentiation of T cells into effector and memory cells. Differentiated effector T cells then need to see antigen AGAIN, which may be presented by carious APCs to activate the effector functions of the T cell in both humoral and cell-mediated immunity.
Capture of PROTEIN antigens by APCs
captured mainly by dendritic cells and concentrated in peripheral lymphoid organs where immune responses are initiated.
Peptide binding to MHC
display for recognition by T cells; each MHC molecule can present only one peptide at a time (because only one binding cleft), but each MHC molecule is capable of presenting many different peptides. MHC can display peptides that are foreign or self (unable to discriminate). We don't develop autoimmune responses because T cells specific for self antigens are either killed or inactivated. MHC I binds to alpha chain MHC II binds to a combo of alpha and beta chain
MHC Molecules
workhorse molecules for presenting antigens Membrane-bound protein of APCs responsible for display of peptide antigens to T cells. Human MHC proteins called human leukocyte antigens (HLA): Main components considered in tissue donation to prevent rejection Two main classes: I and II
Human MHC Locus MHC Class II
1. MHC genes are co-dominantly expressed 2. MHC Class II - three gene sets per locus a. HLA-DP - encodes one α and one β chain b. HLA-DQ - encodes one α and one β chain c. HLA-DR - encodes one α and one or two β chains *Individual inherits 6 to 8 class II MHC alleles*
Human MHC Locus MHC Class I
1. MHC genes are co-dominantly expressed - meaning that alleles inherited from both parents are expressed equally. 2. MHC Class I - each locus contains three genes a. Encode α chains (β2-microglobin gene outside MHC locus) b. Designated HLA-A, HLA-B, HLA-C c. Total 6 MHC Class I molecules (3 genes from each parent)
Identify and recognize the clinical implications of MHC polymorphisms and the co-dominant expression of MHC class I and MHC class II.
1. MHC molecules are highly polymorphic a. Many different alleles are present b. Total different MHC alleles estimated at more than 5000 (2500 different HLA-B alleles alone; Polymorphism of Class II MHC resides in the β genes) 2. *Importance of polymorphism of MHC genes:* a. Some individuals able to respond to any microbe b. Demonstrated in the variable response to vaccines
Conventional Dendritic Cell
majority of dendrites are of this class; specialized types exist depending on the tissue (langerhans cells - epidermis) when these cells encounter microbes at epithelial barriers they are activated and lose their adhesiveness for epithelia and begin to express chemokine receptor CCR7, which is specific for chemoattracting cytokines (chemokines) produces by lymphatic endothelium and by stream cells in the T cell sones of lymph nodes. These chemokines direct the dendritic cells to exit the epithelium and migrate to lymphatic vessels to lymph nodes draining that epithelium.
MHC's are polymorphic...
many different alleles are present among the different individuals in the population. the existence of multiple alleles ensures that there are always some members of the population who will be able to present any particular microbial protein antigen.
Antigen Capture
1. lymph node collect antigen from epithelium and connective tissue 2. blood-borne antigens are captured by antigen-presenting cells in the spleen
Activation and Migration of Dendritic Cells
1. microbe binds to TLR and is phagocytized 2. TLR signaling stimulates secretion of cytokines 3. cytokines activate DCs to lose epithelial adhesiveness and begin to express chemokine receptor, CCR7 4. migrate to T cell zone of lymph nodes - loose afinity for epidermis, release themselves from that area, produce a chemokine receptor that brings them down to the lymph nodes. chemokine at lymh cells that tells receptor on dendritic cell surface to come there.
Describe the pathways of antigen processing for MHC Class I.
1. production of proteins in cytosol 2. proteolytic degradation of proteins 3. transport of peptides from cytosol to ER 4. assembly of peptide-class I complexes in ER 5. surface expression of peptide-class I complexes need to know: class 1 mhc bind with peptides in the ER, then they are moved thru the golgi to the cell surface where they can present. class 1 mhcs not specific: will bind to anything. still need 2 other responses to activate t cell
Describe the pathways of antigen processing for MHC Class II.
1. uptake of extracellular proteins into vesicular compartments of APC 2. processing of internalized proteins in endosomal/lysosomal vesicles 3. biosynthesis and transport of class II MHC molecules to endosomes 4. association of processed peptides with class II MHC molecules in vesicles 5. expression of peptide-MHC complexes on cell surface mhc class 2 never goes to the surface without peptide.
Maturation of Dendritic Cells
mature from cells designed to capture antigens into APCs capable of stimulating T lymphocytes. Maturation is reflected in increased synthesis and stable expression of MHC molecules, which display antigen to T cells. 1. Begin expression of chemokine receptor: specific chemokine secreted by T cell zone of lymph nodes 2. increase expression of molecules for T cell activation: MHC (peptide receptors that bind to T cell receptor); Costimulators (necessary for efficient T cell activation)
Hapten
molecule that is not immunogenic by itself but can react with specific antibody become an immunogen when associated with a carrier protein ex: penicillin; poison ivy
Plasmacytoid Dendritic Cell
named because of morphological resemblance to plasma cells; present in blood and tissue. major source of type I interferons in innate immune responses to viral infections major source of type I interferons in response to viral infection; lets other cells know not to become infected
cross presentation of antigens
one other way that a dendritic cell can present peptides: can engulf an entire infected human cell thats producing/presenting mhc class 1. process it, and then cross present peptides to the cd8 cells. *dendritic cell showing a virus specific CD8 cell 2 things: microbial antigen and costimulator expressed on the APC; thus, T cell becomes activated and differentiates.
Dendritic Cells
phagocytic component of the innate immune system (present in epithelial and subepithelial tissue) "Professional" APC 2 main types: conventional and plasmacytoid