Exam 2: Dr. Pinchuk TCRs and Antigen Recognition Flashcards
How are PRRs developed?
Germline encoded
What kind of specificity do PRRs have?
Broad
What do PRRs recognize?
The presence of microbes or tissue damage
How is the PRR immune response mediated?
By a variety of cells and molecules that are effective against a wide range of pathogens
How are TCRs and BCRs developed?
Gene rearrangement
What kind of specificity do TCRs and BCRs have?
High
What do TCRs and BCRs recognize?
Specific single molecules
What is the TCR and BCR immune response mediated by?
Antigen-specific lymphocytes that are effective against a particular antigen
What does it mean if an immune receptor is germline encoded?
Developed during embryogenesis
They don’t change and the don’t recombine
What makes a TCR similar to IgR (BCR)?
Heterodimer
Antigen-binding site
V and C domains
The 3D structure of the the extracellular domain resembles the Fab fragment of IgR
The genes encoding the TCR chains have a germline organization similar to BCR light and heavy chains
What makes a TCR different from an IgR (BCR)?
No dramatic difference in the size of 2 chains
Always membrane-associated
One antigen-binding site
Antigen recognition function only
No isotype switching of the constant region
What does it mean if a receptor is a heterodimer?
It has alpha and beta chains
What contributes to TCR diversity?
Gene rearrangement
Small insertion or deletions of nucleotides at the joints between gene segments
What does gene rearrangement of TCRs produce?
Sequence variability in the variable regions
Does antigen stimulation promote change in the TCR?
No
What is somatic hypermutation?
When B cells have a second chance to produce diversity
What is T cell development in the thymus initiated by? What does it do?
The assembly of gene segments to make the variable sequence that encodes the V regions of the TCR alpha and beta chains
What is the diversity (D) gene segment involved in?
The random rearrangements that produce the TCR beta chain
What happens during recombination in TCR diversity?
The DNA between gene segments is deleted from the chromosome
Which is more diverse, immunoglobulin or α:β T-cell receptors?
α:β T-cell receptors
Which has more variable segments, immunoglobulin or α:β T-cell receptors?
They are both relatively similar, but beta chains have the most
Which has more diversity segment, immunoglobulin or α:β T-cell receptors?
Immunoglobulin
Which has more V gene pairs, immunoglobulin or α:β T-cell receptors?
α:β T-cell receptors
Which has more junction diversity, immunoglobulin or α:β T-cell receptors?
α:β T-cell receptors
What do RAG genes provide?
The clonal diversity of T and B cell receptors
What do recombinase-activating enzymes encoded by genes RAG-1 and RAG-2 initiate?
V(D)J recombination by nicking double-stranded DNA
What do DNA repair proteins do?
Carry out the rejoining process that brings the gene segment of each type together
What happens if either of the RAG genes is knocked out?
B and T cell development is completely abolished leading to severe combined immunodeficiency
Where have mutations in RAG genes been found?
Human SCID
What do mutations in RAG genes that cause partial enzymatic activity give rise to?
An immunodeficiency called Omenn syndrome
What is the immunological analysis of Omenn syndrome?
Lymphocytes respond poorly to stimulation
No mature B cells and decreased numbers of T cells by FACS analysis
Analysis of genomic DNA from peripheral blood lymphocytes reveals T cell oligoclonality suggesting a defect in RAG genes
RAG-1 and RAG-2 genes were sequenced and a missense mutation was found in RAG-1 gene
What is the immunological analysis of SCID in dogs?
The RAG-1 and RAG-2 genes were sequenced and a missense mutation was found in the RAG-1 gene
What do current approaches to hematopoietic stem cell (HSC) gene therapy involve?
The collection and ex vivo manipulation of HSCs
What is an alternative approach for correcting blood-related diseases?
The direct intravenous administration of viral vectors, AKA in vivo gene therapy
What is the immunological analysis for SCID in horses?
SCID foals are incapable of V(D)J gene rearrangement
DNA protein kinase gene mutation
What does expression of TCR on the cell surface require?
Association with additional proteins
What is the marker for TCR complex?
CD3
What is the function of TCR?
Antigen recognition
What is the function of TCR complex?
Antigen recognition and signal transduction
What is the difference between alpha-beta chains and gamma-delta chains?
Alpha-beta are specific and adaptive
Gamma-delta are innate immune receptor
What does gene rearrangement produce?
Sequence variability in the variable regions
Which produces more diversity, alpha-beta chains or gamma-delta chains?
Alpha-beta
What is different about gamma-delta chains compared to alpha-beta?
Do nor require antigen processing and MHC presentation of peptide epitopes
Express restricted TCR variability
CD4 and CD8 are not commonly expressed
Rarely contribute to functional memory
Where are gamma-delta cells well represented?
Peripheral blood mononuclear cells
Where are gamma-delta cells rarely found?
Lymph node parenchyma
Spleen
Peyer’s patches
Thymus
What percentage of CD3 cells are TCR gamma-delta?
70%
What is the diversity of the TCR V region generated by?
Gene recombination and combinatorial association in all species examined to date
What percentage of blood lymphocytes in humans have gamma-delta TCRs? In ruminants?
5-15%
60%
Where is the subset of TCRs with more limited receptor diversity found? What kind of role does it have?
In the epidermis of the skin and genital tract
Anti-inflammatory and wound healing role
Where is the subset of TCRs with higher receptor diversity found? What does it do?
Secondary lymphoid organs and gut mucosa
Binds to a diverse array of antigens and forms 2 populations, cytokine/chemokine producing and cytotoxic
In immature ruminants and pigs, which T cells are the major circulating population?
Gamma-delta
Do gamma-delta receptors have MHC restriction? What does this mean?
No
They can perform without MHC
