03/06b MHCs & T Cell Receptors

Question 1

How are antigens recognized by T cells?

Answer 1

Antigens must be degraded into peptides in antigen-presenting cells, and presented to T cells on MHC molecules
T cells recognize these peptides through T cell receptors

Question 2

What are the two classes of MHC molecules? How do they differ?

Answer 2

MHC I and MHC II

They have distinct cell distributions and functions, and are recognized by distinct subsets of T cells

Question 3

What determines which MHC will present the antigen?

Answer 3

Source and location of the antigen

Question 4

Which MHC displays cytoplasmic antigens? What types of cells does it activate?

Answer 4

MHC I - displays viral proteins found in the cytosol

Activates CD8 T cells to mature into cytotoxic T cells

Question 5

Which MHC displays endocytosed vesicular antigens? What types of cells does it activate?

Answer 5

MHC II - displays proteins that have been endocytosed (from extracellular bacteria or toxins)
Activates CD4 T cells to mature into helper T cells, which in turn activate macrophages and B cells

Question 6

What cells express MHC I?

Answer 6

All cells!

Question 7

What cells express MHC II?

Answer 7

Antigen-presenting cells

Question 8

Describe the interaction of antigen to MHC receptor

Answer 8

Peptides do not readily dissociate from MHC receptors

Peptide binding contributes to the stability of the MHC receptors

Question 9

Describe the specific binding between MHC I and their peptides

Answer 9

Limited peptide length (8-10 amino acids) due to the MHC binding pocket
Key amino acids in the peptide serve as anchors (degenerate specificity)

Question 10

Describe the specific binding between MHC II and their peptides

Answer 10

Peptides can be 13 amino acids or longer, due to the open ends of the binding pocket
Peptide backbone interacts with conserved amino acids in the binding pocket

Question 11

What are the three MHC I genes?

Answer 11

HLA-A
HLA-B
HLA-C

Question 12

What are the three MHC II genes?

Answer 12

HLA-DR
HLA-DP
HLA-DQ

Question 13

How many MHC I proteins do you express? Why?

Answer 13

Six different MHC I proteins - two different inherited alleles for each class of MHC I
This provides an increased capacity for peptide binding and presentation

Question 14

Predilection for a large number of autoimmune diseases can be predicted from WHAT?

Answer 14

Specific MHC Class II alleles

Question 15

How are peptides loaded onto MHC I?

Answer 15

Proteins are degraded to peptides by the proteasome complex
Peptides are delivered to the ER from the cytosol by TAP, and loaded onto MHC I molecules
MHC I is released from TAP and transported to the cell membrane

Question 16

What distinguished the constitutive proteasome from the immunoproteasome?

Answer 16

The immunoproteasome has specific subunits that are induced by interferon
Interferon can also induce the proteasome to generate peptides that have an affinity for MHC I

Question 17

How do viruses interact with the MHC I processing pathway?

Answer 17

Block it in order to evade the immune system

Different viruses can interfere with peptide transport or peptide loading, or degrade the MHC molecules themselves

Question 18

How are peptides loaded onto MHC II?

Answer 18

Proteins are endocytosed and degraded in acidic endosomes
MHC II molecules are synthesized in the ER, but blocked from binding to any peptides by an appendage protein until they reach the endosome
MHC I is then transported to the cell membrane

Question 19

What is antigen cross-presentation?

Answer 19

The ability of dendritic cells to endocytose viral particles and present them on MHC I in order to activate cytotoxic T cells
Necessary for viruses that do not infect dendritic cells
Antigens are endocytosed and digested in the vesicular compartment, then transported into the cytoplasm and eventually to the ER to be processed and presented on MHC I

Question 20

What happens if you lack MHC I function?

Answer 20

Bare Lymphocyte Syndrome Type I
Patients tend to have chronic bacterial respiratory infections
Can be treated with antibiotics and IVIG

Question 21

What happens if you lack MHC II function?

Answer 21

Bare Lymphocyte Syndrome Type II
Patients present with recurrent bacterial, viral, fungal and protozoal infections in the first year of life
Fatal unless treated with a bone marrow transplant

Question 22

What are class I-like CD1 molecules?

Answer 22

Molecules that are homologous to MHC I, but possess a large hydrophobic binding pocket
Bind primarily to lipids
Present pathogen-derived lipids to T cells, and both self and pathogen lipids to NK cells (have an innate-like function)

Question 23

How do TCRs carry out signal transduction?

Answer 23

Through the CD3 complex - cytoplasmic tails (ITAMs) recruit tyrosine kinases

Question 24

What are TCR co-receptors? What is their function?

Answer 24

Molecules that are required for effective TCR signaling, and bind to MHC simultaneously with TCRs
CD4 is expressed on helper T cells and binds MHC II
CD8 is expressed on cytotoxic T cells and binds MHC I

Question 25

What is MHC restriction?

Answer 25

The recognition by T cells of self MHC proteins complexed with antigen peptide
During development, only T cells that interact weakly with self MHC proteins are selected

Question 26

How are alloantigens recognized in the context of a tissue graft?

Answer 26

Indirectly - alloantigen peptides are presented by self MHC proteins on recipient APCs, and provoke a minor immune response
Directly - intact allogeneic MHC on donor APCs is recognized, which provokes a strong T cell response

Question 27

Why do alloantigens provoke such a large immune response?

Answer 27

Host T cells that recognize self-MHC complexed with foreign peptides may have the capacity to cross-react and recognize allogeneic MHC complex with any peptide
Allogeneic grafts express MHC with MANY peptides, thus activating many cross-reactive T cells

Question 28

What are superantigens?

Answer 28

Whole proteins (NOT peptides) expressed by some bacteria and viruses
Bind to MHC class II molecules outside their binding sites, and to particular TCRs
This results in cross-linking and a potent T cell response (ALL cells that express that particular TCR)
Not an antigen-specific response

Question 29

What are the consequences of superantigen stimulation?

Answer 29

HUGE T cell response (up to 20%)
Massive interferon release, macrophage activation, and cytokine storm
Lots of T cells die
Disrupt your normal immune response - good for bacteria, bad for you

Question 30

List three examples of bacterial superantigens and the disease they cause

Answer 30

Staph enteroxin - food poisoning
Toxic shock syndrome toxin - TSS
Exfoliative toxins A & B - Staph scalded skin syndrome