Generation Of Diversity In The T-Cell Repitoire Flashcards
when can the TCR bind to antigenic peptides?
only when the peptides are in complex with MHC molecules on APC’s
Which immune cells recognise and process antigen?
APC’s!!!!
monocytes
macrophages (terminally differentiated monocytes)
dendritic cells
B cells
macrophages vs dendritic cells?
both rare in peripheral blood - enriched in mucosal tissues
highly phagocytic cells – induce strong T-cell responses and inflammation. Important for protection against Mycobacterium tuberculosis
Macrophages better-equipped to kill pathogens (higher NO production)
DCs better at migrating to lymph nodes (via CCR7) and presenting antigen to T- cells
what 2 things are involved in the commitment of t cells and the process
Notch 1 and Gata3
Notch signals by the thymic stroma
Induction of GATA3
Commitment to the T cell lineage
Intense proliferation
successive stages in T cell development are marked by changes in the surface receptors
Successive stages in T cell development are
marked by changes in surface receptors
• 1 week after arrival of precursors into the thymus progenitors commit to the T cell lineage
• Express early markers of the T cell lineage (CD2 and Thy 1)
• Do not express any of the markers that define T cells later in development or after in the periphery (CD3, CD4, CD8)
• Because of the absence of CD4 and CD8 early developing T cells are called DN (double negatives)
• At DN stage developing T cells (thymocytes) re-arrange the TCR locus
• Stages post DN are characterized by the expression of both CD4 and CD8 and later just one or the other
the t cell receptor
Upon successful rearrangement and in the periphery (if selected) T cells express high levels of TCR chain
TCR is a heterodimer consisting of two transmembrane polypeptide chains covalently linked to each other by
disulphide bonds
Two types alpha-beta and gamma-delta
Each chain has one lg-like N terminal variable domain (V) and one Ig-like constant domain (C), a hydrophobic transmembrane region and a short signalling cytoplasmic region
The V regions of both chains contain short stretches of amino acid sequence that is highly variable between receptors. These regions form the CDRs or complementary determining regions. The 3 CDRs of the alpha chain and 3 of the beta chain form
the peptide-MHC binding site
which segments does the beta chain consist of
v,d and j
which segments does the alpha chain consist of
v and j
is the TCR alone in function
NO
what else works with the TCR
The C regions have cysteines residues that bring the chains together
Charged residues in the transmembrane region bind to CD3 and the zeta chain to form the TCR signalling complex
CD3 and zeta allow for the transduction of signals upon MHC-peptide binding
features of antigens recognised by T cells
- Most t cells recognise peptides and no other molecules
- t cells recognise linear peptides and not conformational determinants of protein antigen
- t cell recognise cell- associated and not soluble antigen
- CD4+ and CD8+ T cells preferentially recognise antigen sampled from the extracellular and cytosolic pools respectively.
what does MHC stand for
Major histocompatibility complex
what does HLA stand for
Human leukocyte antigen
MHC 1 class presents peptides from where
present peptide antigens derived from pathogens that replicate inside cells such as viruses
MHC II class present peptides from where
present peptides from pathogens and antigens that are present outside the cell taken up by endocytosis vesicles of pahgocytic cells
MHC I encodes for which HLA
HLA- A
HLA-B
HLA-C
MHC II encodes for which HLA
HLA-DP
HLA-DQ
HLA-DR
structure of MHC II
• Extracellular peptide binding cleft • Ig-like domain • Cytoplasmic tail • MHC class Il has a conserved CD4 binding site • MHC class I has a conserved CD8 binding site
what does it mean when MHC is polymorphic
there are multiple variants of each gene within the population
what does it mean when MHC is polygenic
It contains several different MHC class I and class Il genes. Thus every individual possesses a set of MHC molecules with different ranges of peptide binding specificities
Polymorphic residue location and MHC-peptide
interactions
• Each MHC has one cleft that binds one peptide at the time but can bind different peptides
• Peptides that bind one MHC share structural features
that promote binding
• Acquire peptides while assembled inside the cell
• Peptide-MHC interactions are storable with low off
rate
• Very small number of MHC-peptide complexes can
activate a T cell
• MHC molecules can bind and display foreign and self
peptide
• MHC class Il bids to longer peptides than class I
which cells are MHC I expressed on
all cells but erythrocyte
which cells are MHC II expressed on
antigen presenting cells
CD4+ cells
helper T cells
secrete cytokines
can only see antigen on MHCII
CD8+ cells
cytotoxic T cells
Kills cells
can only see antigen on MHC I
Pathway of antigen processing and presentation on top of MHC class Il
- uptake of extracellular proteins into vesicular compartments of APC
- processing of internalised proteins in endosomal/ lysosomal vesicles
- biosynthesis and transport of class II MHC molecules to endosomes
- Association of processed peptides with class II MHC molecules in vesicles
- expression of peptides -MHC complexes on cell surface
Properties of the TCR
- Only one form of TCR is expressed on each T cell.
- This means that each T cell and its daughter cells have only one TCR and one specificity for antigen
- This is a T cell clone
- However, there are an infinite number of different versions of the TCR each with a unique antigen binding site.
- A TCR has only one antigen binding site.
- A TCR is never secreted.
which 2 enzymes rearrange the segments
Rag 1 and Rag 2
TCR alpha chain genes
They do not have D gene segments
They are rearranged only after the TCRß chain gene locus has been rearranged.
Successive rearrangements may be attempted until a productive rearrangement has been achieved
junctional diversity
During the joining of different gene segments, addition (or removal) of nucleotides may create new sequences at junctions.
Mediated by TdT terminal deoxynucleotidyl transferase
where does the 2 check point occur during T cell development
- check point for pre-TCR occurs after rearrangement of beta chain
- check point for TCR occurs after rearrangement of alpha genes
Allelic exclusion
Signalling through the pre-TCR suppresses expression of the RAG genes.
So, no more rearrangement at this stage, this is allelic
exclusion.
Allelic exclusion ensures that only one TCRß chain gene is expressed.
These events together are known as ß-selection
