Lecture 5 - Antigen Capture and Presentation

Question 1

Lymphocyte re-circulation

Answer 1

1. Lymphocytes enter lymph nodes, where they encounter APCs
2. Lymphocytes are activated and differentiate in the lymph nodes
3. Lymphocytes exit lymph nodes and enter circulation, head to inflamed tissues where they mediate microbial destruction

Question 2

APC mechanism

Answer 2

APCs capture Ags (antigens) in tissues and transport these Ags to peripheral lymphoid tissues (lymph nodes usually) where lymphocytes are concentrated. They then present those Ags to T cells which activate them

Question 3

MHC

Answer 3

Major Histocompatibility Complex

APCs present peptide antigens to T cells on MHC molecules (they are the holders for APC antigens)

Two types: Class I and Class II
— The Class I and Class II genes code for the Class I and Class II molecules that display peptides to T cells

Question 4

T cell antigens

Answer 4

linear peptides bound and presented by MHC molecules on APCs

Question 4

T cell antigens

Answer 4

linear peptides bound and presented by MHC molecules on APCs

Question 5

MHC Locus

Answer 5

A collection of genes found in all mammals that code for MHC molecules.

The locus contains two sets of highly polymorphic genes (Class I and Class II)

Originally discovered as principle determinant of graft rejection

Question 6

Polymorphism

Answer 6

Multiple alleles of a gene within a population

Question 7

MHC anchoring

Answer 7

MHCs have binding clefts with “pockets”

Side chains of 2 or 3 amino acids of antigen peptides fit into the MHC pockets and “anchor” the peptide in the MHC peptide-binding cleft

Any MHC can present any peptide with the correct anchor residues

(Additional amino acids of the antigen peptide extend upwards and are recognized by TCR. Peptides can remain on display for days)

Question 8

MHC Class I expression

Answer 8

Express viral peptides on nucleated cells
(eg Leukocytes, epithelial cells, mesenchymal cells)

Recognized by activated CD8+ cytotoxic T cells

Question 9

MHC Class II expression

Answer 9

Express microbial peptides on professional APCs, macrophages, and B cells

Recognized by CD4+ helper T cells

Question 10

Class I MHC

Answer 10

Consists of an α chain, noncovalently linked to a β2-microglobulin chain

Polymorphic α1 and α2 domains form a peptide binding groove that holds peptides of 8 - 11 amino acids

The α3 domain is invariant and contacts the T lymphocyte CD8 co-receptor, making it specific to CD8+

Question 11

Class I peptide conversion pathway

Answer 11

Responds to intracellular microbes presented by Class I MHC molecules on the surface of all nucleated cells

1. Microbes (viruses, bacteria) grow and reproduce in the cytoplasm producing their microbial proteins.
2. Results in microbial proteins in the cytoplasm of infected cells.
3. Proteins are cleaved into peptides of varying size and composition by the cytoplasmic proteasome complex.
4. Newly synthesized Class I MHC molecules are loosely attached to the Transporter associated with Antigen Presentation (TAP), a cellular pump that drives transport of cytoplasmic peptides into the E.R.
5. Microbial peptides are pumped into the E.R. lumen by TAP, where they associate with Class I MHC molecules.
6. If a Class I molecule stably binds a microbial peptide, the complex is sent to the cell surface, via the Golgi apparatus and exocytic vesicles
7. Class I MHC - peptide complexes are delivered to the cell surface where they interact with CD8 + T lymphocytes

Question 12

TCR activation in CTL

Answer 12

triggers T lymphocyte differentiation to cytotoxic T lymphocytes (CTL). CTLs kill target infected cells, thereby eradicating the infection

Question 13

CTL

Answer 13

Cytotoxic T Lymphocytes

Question 14

Class II MHC

Answer 14

an α chain, noncovalently linked to a β chain

Polymorphic α1 and β1 domains form a peptide binding groove that holds peptides of 10 - 30 amino acids

The β2 domain contacts the T cell CD4+ co-receptor. Thus, only CD4 + helper T lymphocytes respond to Class II MHC-bound antigens

Question 15

Class II peptide conversion pathway

Answer 15

Responds to extracellular microbes captured by APCs, B lymphocytes, and phagocytes

1. APCs have several means of ingesting microbes.
   — PRR bind microbes.
   — Receptors bind antibodies bound to microbes.
   — APCs sample their environment through pinocytosis.
2. Internalized microbes are delivered to lysosomes.
3. Microbial proteins are cleaved by lysosomal enzymes, yielding numerous microbial peptides of different sizes and configuration
4. In the ER, a protein called the invariant chain, blocks the peptide binding groove of MHC II, preventing peptides associating with MHC II in the ER.
5. Class II molecules are transported to the cell surface in exocytic vesicles.
6. Endosomal vesicles with microbial peptides fuse with exocytic vesicles containing MHC II molecules. Invariant chain is degraded and MHC II binds microbial peptides.
7. If MHC II stably binds a microbial peptide the complex is transported to the cell surface

Question 16

TCR activation in HTL

Answer 16

stimulate B lymphocytes to produce antibodies and phagocytes to ingest and destroy microbes. These pathways are most suited for the destruction of extracellular microbes

Question 17

HTL

Answer 17

Helper T Lymphocytes

Question 18

Co-dominance

Answer 18

Both parental alleles are expressed equally. This means that each individual can express up to 6 different Class I molecules and 10 to 20 different Class II molecules

Question 19

Polymorphism

Answer 19

Multiple MHC alleles means that at least some members of the population will be able to present any given microbial antigen.

Question 20

MHC Peptide Binding Features

Answer 20

— Each MHC molecule displays one peptide at a time
— Broad specificity
— Very slow off-rate
— Stable expression requires peptide
— MHC molecules bind only peptides

Question 21

Costimulators

Answer 21

Provide second signal from APC that triggers T lymphocyte differentiation

Question 22

3 part APC stimulation

Answer 22

• MHC antigen presentation
• Cytokine secretion
• Costimulators