Kuby Immunology: MHC and Antigen Presentation

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Questions and Answers

How do the peptide-binding characteristics of MHC class I molecules differ from those of MHC class II molecules?

  • MHC class I molecules have peptide-binding clefts that are closed at both ends. (correct)
  • MHC class I molecules present peptides with anchor residues distributed along the length of the peptide.
  • MHC class I molecules generally bind larger peptides than MHC class II molecules.
  • MHC class I molecules have peptide-binding clefts that are open at both ends.

What is the predominant role of the TAP complex in antigen processing?

  • It facilitates the transport of peptides from the endoplasmic reticulum to the cytosol.
  • It transports peptides from the cytosol into the endoplasmic reticulum for MHC class I loading. (correct)
  • It prevents MHC class II molecules from binding to peptides in the endoplasmic reticulum.
  • It loads peptides onto MHC class II molecules within endocytic vesicles.

Which of the following best describes the function of the invariant chain (Ii) in MHC class II antigen presentation?

  • It promotes the loading of antigenic peptides onto MHC class I molecules in the ER.
  • It stabilizes the interaction between the T-cell receptor and the MHC class II molecule.
  • It facilitates the assembly of MHC class I molecules with $\beta_2$-microglobulin.
  • It prevents MHC class II molecules from binding peptides in the endoplasmic reticulum and directs MHC class II molecules to endocytic compartments. (correct)

How does the binding of a superantigen to MHC class II molecules and T-cell receptors differ from that of a conventional peptide antigen?

<p>Superantigens bind to the MHC class II molecule and the T-cell receptor outside of the peptide-binding groove. (A)</p> Signup and view all the answers

What is the significance of the polygenic nature of MHC genes in the context of immune responses?

<p>It increases the likelihood that an individual will be able to present a wide variety of antigens. (B)</p> Signup and view all the answers

Which cellular process is directly inhibited by the presence of the CLIP (Class II-associated Invariant chain Peptide) molecule?

<p>The binding of antigenic peptides to MHC class II molecules within endosomes. (C)</p> Signup and view all the answers

Which of the following statements accurately compares the structure of MHC class I and MHC class II molecules?

<p>MHC class I molecules consist of one transmembrane glycoprotein paired with $\beta_2$-microglobulin, whereas MHC class II molecules consist of two transmembrane glycoproteins. (B)</p> Signup and view all the answers

What is the primary consequence of a genetic defect that impairs the function of the TAP transporter?

<p>Impaired presentation of cytosolic antigens via MHC class I molecules. (B)</p> Signup and view all the answers

Which cellular compartment is the primary site for the loading of peptide antigens onto MHC class II molecules?

<p>Lysosomes and endosomes. (B)</p> Signup and view all the answers

What is the role of calreticulin and tapasin in MHC class I antigen presentation?

<p>To stabilize the MHC class I molecule and facilitate peptide loading in the ER. (D)</p> Signup and view all the answers

The diversity of T-cell receptors (TCRs) is generated through somatic recombination of gene segments. Which of the following gene segments are rearranged to form the variable region of the TCR $\beta$ chain?

<p>V, D, and J segments. (B)</p> Signup and view all the answers

In T-cell development, what is the significance of positive selection?

<p>It ensures that T cells can recognize and respond to antigens presented by MHC molecules. (C)</p> Signup and view all the answers

Which of the following statements best describes the role of CD3 molecules in T-cell activation?

<p>CD3 molecules are transmembrane signaling components of the T-cell receptor complex. (B)</p> Signup and view all the answers

What is the function of the immunological synapse formed between a T cell and an antigen-presenting cell (APC)?

<p>To concentrate signaling molecules and adhesion factors for efficient T-cell activation. (C)</p> Signup and view all the answers

Which of the following is an immediate early event in T-cell activation following T-cell receptor engagement?

<p>Phosphorylation of ITAMs on CD3 molecules by Lck kinase. (B)</p> Signup and view all the answers

How does the mechanism of action differ between CTLA-4 and CD28 in regulating T-cell activation?

<p>CTLA-4 delivers an inhibitory signal by outcompeting CD28 for B7 binding on antigen-presenting cells. (D)</p> Signup and view all the answers

What is the outcome of T-cell anergy when a T cell recognizes its cognate antigen on an APC that lacks co-stimulatory molecules?

<p>The T cell becomes unresponsive to subsequent antigen stimulation, even with co-stimulation. (A)</p> Signup and view all the answers

Superantigens can activate a large proportion of T cells, leading to excessive cytokine production. What region of the T-cell receptor do superantigens bind to?

<p>The variable region of the TCR $\beta$ chain. (B)</p> Signup and view all the answers

Which of the following is a key function of IL-2 (Interleukin-2) in T-cell activation?

<p>It promotes T-cell proliferation and survival. (C)</p> Signup and view all the answers

What is the primary function of negative selection during T-cell development in the thymus?

<p>To eliminate T cells that strongly react to self-antigens, preventing autoimmunity. (D)</p> Signup and view all the answers

What is the role of the co-stimulatory molecule B7 in T-cell activation?

<p>It interacts with CD28 on the T cell to provide a signal required for T-cell activation. (D)</p> Signup and view all the answers

In the context of T-cell activation, what is the function of ZAP-70?

<p>It phosphorylates downstream signaling molecules, leading to T-cell activation. (A)</p> Signup and view all the answers

How does the process of positive selection in T-cell development ensures self-MHC restriction?

<p>By promoting the survival of T cells that can recognize and bind to self-MHC molecules. (A)</p> Signup and view all the answers

What is the role of Lck kinase in T-cell receptor signaling?

<p>It phosphorylates the ITAMs on the CD3 molecules. (B)</p> Signup and view all the answers

What describes the distribution and function of adhesion molecules, such as LFA-1 and ICAM-1, in T-cell activation?

<p>They stabilize the interaction between the T cell and the antigen-presenting cell. (B)</p> Signup and view all the answers

Which of the following is the primary mechanism by which T cells undergo apoptosis?

<p>Activation of the Fas/FasL pathway. (A)</p> Signup and view all the answers

How are the genetic rearrangements that contribute to T-cell receptor diversity mediated?

<p>By V(D)J recombinase. (B)</p> Signup and view all the answers

What would be the most likely outcome if a genetic mutation disabled the expression of MHC class II molecules?

<p>Impaired activation of CD4+ T cells. (A)</p> Signup and view all the answers

Which of the following best explains how a dendritic cell initiates T-cell activation?

<p>By presenting antigenic peptides on MHC molecules and providing co-stimulatory signals. (D)</p> Signup and view all the answers

What is the significance of the ITAMs (immunoreceptor tyrosine-based activation motifs) in T-cell activation?

<p>They serve as docking sites for signaling molecules, initiating downstream signaling pathways. (D)</p> Signup and view all the answers

How does a fixed antigen-presenting cell (APC) – one lacking co-stimulatory molecules – influence T-cell activation?

<p>It induces T-cell anergy. (A)</p> Signup and view all the answers

Given its role in T-cell activation, what direct effect would a drug that inhibits the interaction between CD28 and B7 have?

<p>Inhibited T-cell proliferation. (D)</p> Signup and view all the answers

Which process is directly associated with the release of cytochrome c from the mitochondria during T cell apoptosis?

<p>Formation of the apoptosome. (B)</p> Signup and view all the answers

What is the primary significance of the observation that T cells in G0 state before activation?

<p>Allows for controlled responses and prevents uncontrolled proliferation. (B)</p> Signup and view all the answers

Which of the following surface interactions is required for T cell activation?

<p>TCR and peptide-MHC. (B)</p> Signup and view all the answers

How does negative selection impact T-cell development and overall immune function?

<p>Eliminates self-reactive T cells, preventing autoimmune responses. (C)</p> Signup and view all the answers

Which component of the T-cell receptor complex is directly responsible for transducing the activation signal into the cell?

<p>Costimulatory signals. (B)</p> Signup and view all the answers

Which of the following outcomes can happen to a T-cell presented with antigen in the absence of sufficient co-stimulation?

<p>Anergy development. (A)</p> Signup and view all the answers

Flashcards

Major Histocompatibility Complex (MHC)

A complex of genes encoding MHC class I and II molecules, and proteins involved in antigen processing.

MHC class I function

Present peptides derived from intracellular pathogens to T cells.

MHC class II function

Present peptides derived from extracellular pathogens to T cells.

β2-microglobulin

Non-covalent association with MHC class I molecule; stabilizes the structure.

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Peptide-binding cleft

The region of the MHC molecule that binds to the peptide.

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Class I MHC characteristics

α1/α2; closed at both ends; binds 8-10 amino acids. Anchor residues at both ends of peptide

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Class II MHC characteristics

α1/β1; open at both ends; binds 13-18 amino acids. Amino acid anchor residues distributed along the length of the peptide

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Antigen processing

Proteins are degraded into peptides for presentation by MHC molecules.

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Cytosolic pathway

Intracellular pathogens are processed via cytosolic pathway for MHC class I presentation

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Endocytic pathway

Extracellular pathogens are processed via the endocytic pathway for MHC class II presentation.

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Transporter Associated with Antigen Processing (TAP)

Transport peptides from the cytosol to the endoplasmic reticulum for MHC class I loading.

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Invariant chain (Ii)

Prevents peptides from binding to MHC II in the ER.

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HLA-DM

MHC class II-like molecule that removes the invariant chain peptide (CLIP).

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T-cell Receptor (TCR)

Binds peptides presented by MHC molecules to T-cells.

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αβ T cells

The CD3+ T cell count in normal range is 90-99%

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Combinatorial Diversity

Joining V, D, and J gene segments.

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N-region addition

The addition of nucleotides between gene segments.

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CD4 and CD8

Stabilizes interaction of T cells with MHC molecules.

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CD4+ T cells

TH cells that develop in the thymus and recognize class II MHC.

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CD8+ T cells

TC cells that develop in the thymus and recognize class I MHC.

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Class I MHC knockout

CD4+ T cells, CD8+ T cells, CD4-CD8- T cells are positive.

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T cell maturation

A process ensuring T cells don't react to self antigens but do react to non-self antigens.

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Engagement Signal

A signal that activates T cells.

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T-Cell Activation Genes

Immediate genes such as proto-oncogenes, cellular oncogenes and transcription factor.

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Anergic genes

T cells can't proliferate and are unresponsive due to only one signal being delivered

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Costimulatory Activity

B7 molecules bind to CD28 molecules to start a T-cell response

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No proliferation

Interaction between T cells and MHC or B7 and CD28 are interrupted.

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Superantigens

Bind non-specifically to MHC class II and TCR leading to widespread T cell activation.

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Memory T-cell

A normal APC and CD28 are necessary for proliferation of Memory T cells.

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Apoptosis

FasL molecules on T-cells interact with Fas molecules on target cells to induce ____________.

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Study Notes

  • Kuby Immunology, Sixth Edition, Chapter 8 is about the Major Histocompatibility Complex and Antigen Presentation
  • The copyright for this edition is 2007 by W. H. Freeman and Company

Mouse H-2 Complex

  • Encoded on chromosome 17 in mice.
  • Includes Class I, Class II, and Class III genes.
  • Class I region contains the K and D regions.
  • Class II region contains the IA and IE regions.
  • Class III region contains the S region, encoding complement proteins and TNF-α/TNF-β.
  • Not all haplotypes express H-2L.

Human HLA Complex

  • MHC genes are encoded on chromosome 6 in humans.
  • Includes Class I, Class II, and Class III genes.
  • Class I region contains the B, C, and A regions.
  • Class II region contains the DP, DQ, and DR regions.
  • Class III region contains the C4, C2, and BF regions.
  • All regions have various gene products, such as HLA-A, HLA-B, etc.

Class I MHC Molecule

  • Has 3 membrane-distal domains: α1, α2, and α3.
  • The α1 and α2 domains form the peptide-binding cleft.
  • It has 1 membrane-proximal domain: α3 (Ig-fold structure).
  • β2-microglobulin associates with Class I molecules.
  • Includes a transmembrane segment and a cytoplasmic tail.

Class II MHC Molecule

  • Has 2 membrane-distal domains: α1 and β1.
  • Has 2 membrane-proximal domains: α2, β2.
  • Α1 and β1 domains form the peptide-binding cleft.
  • Includes a transmembrane segment and a cytoplasmic tail.
  • B2/α2 have structural similarity to FC

Class I and Class II DNA & mRNA

  • Class 1 Molecules are made from various components
  • Includes Leader (L), α1, α2, α3, transmembrane(Tm) and cytoplasmic domains (C C)
  • Components of molecule are used together for assembly
  • Class II Molecules have similar structure and order of assembly as Class 1

Peptide Binding by Class I and Class II

  • Class 1 molecules are closed on both ends, and Class II molecules are open at both ends
  • Common peptide motifs involved in binding
  • Class 1 bind 8-10 amino acids with hydrophobic carboxyl-terminal anchor
  • Class 2 bind 13-18 amino acids with residues distributed along the length of the peptide

MHC Proteins

  • MHC proteins are polygenetic
  • Cells can have 1,000-4,000 proteins each
  • Can have up to 100,000 proteins per cell

Antigen Processing

  • Antigen must be degraded into peptides for presentation
  • APCs present antigen
  • Fixation is a necessary part of the process

Cytosolic Pathway

  • Endogenous antigens are processed.
  • This pathway involves the proteasome and TAP (Transporter Associated with Antigen Processing).
  • Ubiquitin mediates this process
  • Peptide-class 1 MHC complex happens here

Endocytic Pathway

  • Exogenous antigens are broken down in endocytic compartments
  • The peptides binds to class II MHC
  • Peptides are created in peptide-class II MHC complex

Tapasin

  • Tapasin is a TAP-associated protein
  • It forms the molecular complex that prevents MHC I from binding
  • Calreticulin, and ERp57 also involved
  • B2-microglobulin is also key

Endocytic Pathway

  • Invariant chains prevent MHC II from binding peptides
  • HLA-DM causes exchanged of CLIP for antigenic peptide
  • The endosome containing antigen can be accessed at a low PH of 4.5-6

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