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48 Cards in this Set
- Front
- Back
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What is the function of the MHC
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MHC is a set of closely linked genetic loci tht are important for graft. This set of linked loci is highly polymorphic and play a central role in control of the cellular interactions responsible for physiological immune responsiveness.
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What are the genes in Class I loci and what are there fx
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HLA A
HLA B HLA C these molecules are present on virtually all nucleated cells present antigen to CD8+ T lymphocytes |
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What are the genes in Class II loci and what are there fx
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HLA D Subset loci: DR, DQ, DP
these molecules are found on dendritic cells, B-lymphocytes and macrophages present antigen to CD4+ T lymphoctyes |
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What are the genes in Class III loci and what are there fx
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DO NOT PRESENT ANTIGEN TO T-LYMPHOCTYES
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Describe the structure of the Class I loci molecules
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1 a chain, the Class I polypeptide and one light chain B2 microglobin
total weight is 44000 daltons for the a chain and 12000 daltons for the B2 chain. a chain is made up of polymorphic a1, a2, a3. B chain is non-polymorphic Binds short peptides of about 9aa in length |
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Describe the structure of the Class II loci molecules
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MHC Class II molecules has 2 polypeptide chains per molecule
2 a and 2 B chains can bind peptides 13-17aa in length |
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What is the diff between peptide binding to MHC Class I molecule and peptide binding to Class II molecule
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ANCHOR residues that bind a particular MHC CLass I molecule do not need to be identical but are always related. Peptides also bind class I MHC molecules through their amino and carboxy termini.
ANCHOR residues that bind a particular MHC class II molecule do not need to be identical but are always related. Peptide bind MHC at the peptide binding cleft based on the anchoring residues. |
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On what chromosome is HLA complex found?
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the short arm of chromosome 6
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Cell surface expression of MHC Class I and Class II molecules
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MHC class Ia chains and MHC class IIa chain and B chains are encoded by separate genes of MHC locus
B2 microglobulin is not encoded within the MHC region of Chromosome 6 These genes encode for proteins that associate in the ER and shuttle to the cell surface where they are mem glycoproteins. |
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Co-dominant Expression of MHC Antigens
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Each individual expresses in a co-dominant fashion the class I and class II genes of both chromosomes 6.
Thus each individual expresses 3 maternal and 3 paternal class I molecular types, as well as 3 maternal and 3 paternal class II molecular types on cells that express both class I and class II. Each individual has two "half sets" (haplotypes) of genes. One haplotype is inherited from each parent. Both of these haplotypes are expressed equally. |
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Co-dominant expression of MHC alleles
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With the exception of the DR a locus the number of diff alleles (the variant genes that can occupy the locus) for class I and class II MHC genes is very large.
The high degree of polymorphism in nucleotide sequence results in a high degree of polymorphism in aa sequence. The polymorphisms are located at specific sites within the MHC molecules. The differences in aa seq allow for peptide binding and for T lymphocyte recognition. |
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What is the advantage to all the polymorphisms and high variability?
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Polymorphisms confer a selective advantage
High variability allows MHC cell to present many many different antigens. |
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Cellular Interactions
How does a specific T cell recognize antigen? |
A specific T cell response to Antigen on cell surfaces depends NOT on recognition of the Ag alone but on recognition of an antigenic peptide in the groove of an MHC molecule on the cell surface.
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What is the difference between the CD8+ and CD4+ specificities?
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Cytolytic T lymphoctyes (CD8+) are specific for foreign antigen plus products of class I loci
T helper (CD4+) lymphocytes are specific for foreign antigen plus products of the class II loci. |
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What is MHC restriction?
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The dependence of the T cells specific reactivity on foreign antigen plus MHC products rather than on foreign antigen alone is called MHC restriction.
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Describe two cellular reactions when MHC restriction is importatnt.
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MHC restriction- Lymphoctyes typically interact with foreign antigen recognized by the lymphoctye in the CONTEXT of host (self)-MHC molecules. Cellular reactions in which such MHC interactions are important include:
- The ctyolysis of target cells by ctyolytic T lymphoctyes (CD8+) - T lymphocyte-antigen presenting cells (macrophages, dendritic cells, B lymphocytes) interactions associated with T lymphoctye production of ctyokines (CD4+). |
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How do Cytotoxic T lymphoctyes recognize antigen?
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Cytotoxic T lymphoctyes (CD8+) are elicited by host cells that carry foreign antigens
The specificity of the T killer cells for the viral peptide in the context of a host cell's class I determinant allows cytotoxic T cell to recognize the complex of viral peptide with MHC class I and kills the infected cell Point: even more specificity |
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The human leukocyte antigen complex (HLA):
A. Elicits graft rejection B. Restricts immune responses C. Is the major histocompatibility complex for humans. D. Functions physiologically to present antigen E. all of the above |
Answer is all of the above because
HLA plays a major role in graft rejection restricts immune response to not just foreign antigen but to foreign antigen and the context of the MHC molecule HLA is the major histocompatibility complex for humans HLA present antigen to CD8+/CD4+ cells |
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If B lymphoctyes are not phagoctyic then how do they serve as Antigen Presenting Cells
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They bind antigen via BCR, internalize it, degrade it and then present it on their surface.
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What are the 3 types of antigen presenting cells?
How are they similar/different |
3 TYPES
-Macrophages or mononuclear phagoctyes -Dendritic Cells -B lymphoctyes All APCs are Class II but B lymphocytes are not phagoctyic |
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How do macrophages, DCs and B lymphocytes differ in their antigen presentation?
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Macrophages prime purpose is to phagocytize antigen and present them via Class II (also class I) to T lymphoctyes
Dendritic cells are not particularly good at presenting antigen when they first encounter it but are particularly good at phagocytosis. Through a process of maturation they process that antigen express costimulatory molecules and then present that antigen very effectively after maturation. B lymphoctyes present antigen on their surface but are specific for one antigen through its B cell receptor BCR |
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Explain Class I antigen processing
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Peptides derived from the cytoplasm are loaded onto class I MHC molecules.
Process: virus -> degraded by host cell proteasomes -> peptides in cytoplasm-> transported into ER by TAP-1 and TAP-2 -> newly made MHC Class I molecules assemble in ER binds peptides -> transported to Goldgi -> to cell surface |
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Explain Class II antigen processing
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Class II
phagoctyic cell takes up antigen -> degrade to peptides -> peptides in endosomal compartment loaded onto class II molecule -> present peptide to T cell. |
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Explain B cell antigen processing
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B cell bind to antigen by BCR/ antibody -> brought inside cell into an endosomal compartment where antigen is degraded into peptides -> loaded onto class II MHC and presented to T cells on cell surface.
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Compare the 3 TYPES of antigen processing.
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B cell take up antigen by BCR and phagocytic cells engulf the bacteria and then present it in context of class II
Endogenous antigen is presented by Class I Exogenous antigen is presented by Class II |
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Where are the antigenic peptides made?
How are they degraded? |
Antigenic peptides that bind to MHC class I molecules are typically derived from viruses that take over the biosynthetic machinery of the cell. These proteins are made in the cytosol of the ER and are degraded by passing through barrel shaped structures called proteasomes
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How do proteins move from the Cytoplasm to the ER?
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The proteasome is made up of 2 subunits LMP2 and LMP7
Proteins are made linear by passing thru this barrel shaped structure of the proteasome producing peptide fragment which are transported by Transporters Associated with Antigen Processing, TAP-1 and TAP-2 which allow peptide to be release in the ER . |
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Where are MHC molecules produced?
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THE ER
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What is the function of Tapasin?
What is the function of a chaperone molecule? |
Tapasin allows for the nacent, uncompletely folded protein to bind to a site close to TAP where the peptides will be used. Chaperones hold the MHC class I molecule in conformation. Once a peptide with high affinity interacts with the MHC class I molecule the chaperones are released and it is not an appropriately folded MHC class I molecule that can move to the surface and present peptides to CD8+ T lymphoctyes
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What is the signal that causes Class I MHC molecule to be sent to the cell surface?
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the only way a class I molecule is transduced to the cell surface is if it has a peptide bound to the peptide binding cleft.
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How do proteasomes work?
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Inside the proteasome are enzymes that cleave the linear proteins so only proteins that pass through proteasome are cleaved
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What are the functions of chaperone proteins?
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In ER are where MHC molecules are produced, nacent MHC molecule is chaperoned by Calnexin. Partly folded MHC class I a chains bind to calnexin until B2-microglobulin binds
Calnexin is released and the αβ₂-microglobulin complex binds calreticulin and Erp57 chaperon proteins and binds nacent unfolded protein close to TAP via tapasin. |
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Describe MHC Class II antigen processing.
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Phagocytic cell picks up one antigen. The antigen are degraded enzymatically in endosomes and lysosomes, into peptides that bind MHC class II molecules. The acidified endosome that picks up the antigen has a low pH which activates the proteases and degrade the peptides into very small antigen particles about 13-18 aa. They are loaded into the Class II MHC.
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How is the MHC Class II molecule transported to the cell surface.
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When a particular Class II molecule is synthesized in the ER it is synthesized with the invarient chain Ii. Ii occupies peptide binding cleft so that peptides in ER do not bind. Ii prevent peptides in the ER from binding. Transits to a series of Endosomoal compartments. Ii is cleaved in an acidified such that only one small part called CLIP occupies this particular peptide binding groove. Then as the cell matures DM is a peptide loader and unloader. Unloads clip until the affinity of the peptide is so high DM cannot remove the peptide from the groove. MHC transfers to the cell surface to present it to CD4+ molecules
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What is DO? What does it do?
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DO is comprised of an alpha and beta. Inhibits DM found in thymus.
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Compare the process of peptide loading for MHC Class I and class II molecules.
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Class II loading is a conseq. of engulfing of exoge
Class I antigen processing is a conseq of loading of intracellular peptides Class II MHC is synthesized in ER with Ii which is later removed leaving CLIP and gets to cell surface by DM action. Class I MHC has to be loaded with a peptide bound in the groove to be transported to the cell surface. |
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If no foreign antigen is present in the body, how does any class I get to the cell surface?
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an antigen peptide is needed in the peptide binding cleft
in the cleft of a person with no foreign antigen is self-peptide MHC class I molecules under normal conditions (no foreign antigen) are loaded with self peptides derived from the normal degradation of self cellular proteins. |
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Describe the means of recognition for the CD4+ T lymphoctyes
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CD4+ T lymphoctyes do not recognize free or soluble antigens -> they recognize antigen on the surface of APCs in the context of Class II molecules.
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Describe MHC restriction in the context of antigen processing and presentation.
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The interaction btwn T lymphocytes and antigen and the class II molecule is highly specific and will result in specfic T cell proliferation and differentiation. These lymphoctyes are said to be genetically restricted by the class II molecule on which the antigenic determinants were first recognizd.
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What are the two effector functions of CD4+ T lymphoctyes
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CD4+ T lymphocytes can either mediate macrophage activation or act as helper cells in antibody responses (by secreting cytokines).
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What are the two subsets of CD4+T lymphoctyes?
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Th1 produces cytokines which activates macrophages
Th2 recognize antigenic peptide with MHC class II and activates B cell which induce antibody synthesis |
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How do APCs like Dendritic Cells converted from immature to mature cells?
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Immature/resting APCs such as dendritic cells are highly phagocytic but do not present antigen well.
During the innate immune resp. and after phagocytosis they mature and present antigen well to T cells. Mature dendritic cells express on their cells surface: antigen + costimulatory molecules e.g. B7 aka CD80 and CD86 + large amts of cytokines to cause T lymphocyte prolif. and diff. |
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How are Naïve T cells activated?
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Activation of naïve T cell by antigen req. 2 signals.
1) presentation of peptides by MHC class II 2) interaction between B7 on the APC and CD28 on the membrane of the T cell. The regulated expression of co-stimulatory molecules ensures that naïve T lymphocytes are activated only at the correct time and place. |
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Can APCs that lack co-stimulatory B7 still activated T cells?
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APCs that have taken up an antigen (not a microorganism) do not necessarily express B7.
T cells that recognize peptides expressed by MHC class II on the surface of the APC are stimulated to express CD40 ligand, CD40L aka CD154. CD40L engages CD40 on the surface of the APC and this signal induces the expression of B7 by the APC. CD28 ligation of B7 induces T cell proliferation and differentiation. |
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What cellular reactions are required for production of antibodies?
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✦ Production of antibody to most antigens requires not just B cells but also T cells.
✦ B cells that display processed peptides on MHC class II molecules also express B7. ✦ T cells recog MHC presented antigen and B7 co-stimulates CD28 on the surface of the T cell to activate the naïve T cell. This activation induces the expression of CD40L which engages CD40 on the surface of the B cell, activating the T cell to produce ctyokines, allowing the B cell to prolif. and diff into plasma cells that secrete antibody |
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What is the immune synapse?
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an aread of contact between an armed effector T cell and its contact forms an immune synapse
is defined by a specific pattern of receptor segregation with a central cluster of TCRs surrounded by a ring of adhesion molecules (like LFA-1) |
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What is the function of the immune synapse?
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provides a mechanism for sustained TCR engagement and signaling
provides a higher-order molecular mechanism of junction formation, MHC-peptide transport and cluster stabilization |
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Describe the structure of the immune synapse
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a central cluster within concentric rings
the intermediate ring is enriched in adhesion molecules (like LFA-1:ICAM-1) that promote efficient TCR-MHC-peptide interaction leading to biological response. LFA-1 is on the T cell surface and I-CAM-1 is on the APC surface. The inner circle contains TCR, CD4 and costimulatory molecules (like CD28). |
