T Cell Receptors Flashcards
PRRs
- 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
TCRs and BCRs
- 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
TCR structure similarities with IgR
- 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
TCR structure differences with IgR
- 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
TCR diversity
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
Antigen stimulation ______ promote change in TCR
Does not!
- no equivalent of somatic hypermutation of the antigen-binding site
Gene rearrangement
- 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
D gene segment
“diversity”; involved in random rearrangements that produce the TCR beta chain
Recombination
During recombination the DNA between gene segments is deleted from the chromosome
Where does gene rearrangement occur?
Thymus
RAG
Plays important role in joining the gene segments with extra DNA being deleted
- occurs during TCR alpha chain formation
DNA hairpin
Formed at place of DNA deletion
- enzymes, including DNA dependent protein kinases, cleave the hairpin
TdT
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
TCR vs immunoglobulin diversity
Alpha/beta TCRs have higher levels of:
- V gene pairs
- junctional diversity
- total diversity
Adaptive immunity specific genes
RAG genes
- recombinase-activating enzymes encoded by RAG-1 and RAG-2 initiate V(D)J recombination by nicking dsDNA
What happens if RAG-1 or RAG-2 are knocked out?
B and T cell development is completely abolished, leading to severe combined immunodeficiency in mice
- RAG mutations have been found in human SCID
Omenn syndrome
Mutations that cause partial enzymatic activity
SCID in dogs
Frisian Water Dogs
- showed reduced Ig and lymphocyte levels
- RAG-1 gene had a missense mutation
- treatment: bone marrow transplant (future)
SCID gene therapy in dogs
Hematopoietic stem cell gene therapy involve collection and ex vivo manipulation of HSCs
- alternative: direct IV administration of viral vectors (in vivo)
Foamy viruses
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
SCID in horses
Foals are incapable of V(D)J gene rearrangement
- DNA-PK (protein kinase) gene mutation
- treatment: bone marrow transplantation
TCR complex
Expression of TCR on the cell surface requires association with additional proteins
TCR vs TCR complex functions
TCR: antigen recognition
TCR complex: antigen recognition + signal transduction
Alpha/beta and gamma/delta similarities
Gene rearrangement produces sequence variability in the variable regions
- gamma/delta produces a smaller amount of diversity than alpha/beta
