T Cell Receptors

Question 1

PRRs

Answer 1

• germline encoded (occurs during embryogenesis)
• broad specificity
• recognize the presence of microbes or tissue damage
• immune response is mediated by a variety of cells and molecules that are effective against a wide range of pathogens
• innate immunity

Question 2

TCRs and BCRs

Answer 2

• gene rearrangement
• highly specific
• recognize specific single molecules
• immune response is mediated by antigen-specific lymphocytes that are effective against a particular antigen
• adaptive immunity

Question 3

TCR structure similarities with IgR

Answer 3

• heterodimer (alpha/beta chains)
• antigen binding site
• V and C domains
• 3D structure of the extracellular domain resembles the Fab fragment of IgR
• genes encoding the TCR chains have a germline organization similar to BCR heavy and light chains

Question 4

TCR structure differences with IgR

Answer 4

• no dramatic difference in the size of 2 chains (BCR have light/heavy chains, TCR have no size differences)
• always membrane associated
• 1 antigen binding site (BCRs have 2)
• antigen recognition function only (no effector function!)
• no isotype switching of the constant region

Question 5

TCR diversity

Answer 5

Gene rearrangement produces sequence variability in the variable regions
- small insertions or deletions of nucleotides at the joints between gene segments further contribute to diversity

Question 6

Antigen stimulation ______ promote change in TCR

Answer 6

Does not!

- no equivalent of somatic hypermutation of the antigen-binding site

Question 7

Gene rearrangement

Answer 7

• T cell development in the thymus is initiated by the assembly of gene segments to make the variable sequence that encodes the V regions of the TCR alpha and beta chains

Question 8

D gene segment

Answer 8

“diversity”; involved in random rearrangements that produce the TCR beta chain

Question 9

Recombination

Answer 9

During recombination the DNA between gene segments is deleted from the chromosome

Question 10

Where does gene rearrangement occur?

Answer 10

Thymus

Question 11

RAG

Answer 11

Plays important role in joining the gene segments with extra DNA being deleted
- occurs during TCR alpha chain formation

Question 12

DNA hairpin

Answer 12

Formed at place of DNA deletion

- enzymes, including DNA dependent protein kinases, cleave the hairpin

Question 13

TdT

Answer 13

Terminal deoxynucleotidyl transferase
- inserted at single-stranded DNA end between V and J gene segments
- random addition of nucleotides within coding joint
= complete alpha chain variable region

Question 14

TCR vs immunoglobulin diversity

Answer 14

Alpha/beta TCRs have higher levels of:

• V gene pairs
• junctional diversity
• total diversity

Question 15

Adaptive immunity specific genes

Answer 15

RAG genes

- recombinase-activating enzymes encoded by RAG-1 and RAG-2 initiate V(D)J recombination by nicking dsDNA

Question 16

What happens if RAG-1 or RAG-2 are knocked out?

Answer 16

B and T cell development is completely abolished, leading to severe combined immunodeficiency in mice
- RAG mutations have been found in human SCID

Question 17

Omenn syndrome

Answer 17

Mutations that cause partial enzymatic activity

Question 18

SCID in dogs

Answer 18

Frisian Water Dogs

• showed reduced Ig and lymphocyte levels
• RAG-1 gene had a missense mutation
• treatment: bone marrow transplant (future)

Question 19

SCID gene therapy in dogs

Answer 19

Hematopoietic stem cell gene therapy involve collection and ex vivo manipulation of HSCs
- alternative: direct IV administration of viral vectors (in vivo)

Question 20

Foamy viruses

Answer 20

Comprise major subfamily of retroviruses with properties ideal for HSC gene therapy
- IV injection of foamy virus carrying corrective gene = immune cell development in canine with SCIDS

Question 21

SCID in horses

Answer 21

Foals are incapable of V(D)J gene rearrangement

• DNA-PK (protein kinase) gene mutation
• treatment: bone marrow transplantation

Question 22

TCR complex

Answer 22

Expression of TCR on the cell surface requires association with additional proteins

Question 23

TCR vs TCR complex functions

Answer 23

TCR: antigen recognition

TCR complex: antigen recognition + signal transduction

Question 24

Alpha/beta and gamma/delta similarities

Answer 24

Gene rearrangement produces sequence variability in the variable regions
- gamma/delta produces a smaller amount of diversity than alpha/beta

Question 25

Gamma/delta versus alpha/beta differences

Answer 25

- do not require antigen processing and MHC presentation - express restricted TCR variability - CD4 and CD8 are not commonly expressed (considered double negative cells) - rarely contribute to functional memory

Question 26

Where are gamma/delta cells located?

Answer 26

Well represented among peripheral blood mononuclear cells and in afferent/efferent lymph - are rarely found in lymph node, parenchyma, spleen, Peyer's patches, and thymus

Question 27

Species differences

Answer 27

- Diversity of TCR V region is generated by gene recombination in all species unlike B cell diversity - gamma/delta TCRs found in 5-15% of blood lymphocytes in humans and mice, and up to 60% in ruminants

Question 28

Immature ruminants and swine

Answer 28

Gamma/delta T cells are a major circulating population

Question 29

Unique mechanisms of adaptive immunity improve pathogen ____, rather than pathogen ____

Answer 29

Recognition; destruction

Question 30

T and B lymphocytes recognize and bind antigens via

Answer 30

Highly variable antigen specific receptors

Question 31

_____ have more diverse roles involving interactions with other cells

Answer 31

T cells

Question 32

TCR expression requires association with the _______ to transmit signals to the interior of the cell upon antigen recognition

Answer 32

CD3 protein complex

Question 33

What explains the critical differences between TCR and BCR

Answer 33

TCR uses other molecules for effector function