Lec 13: Space Time and TcR Flashcards
How long does it take immune cells to recirculate in the body
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Where do key cell-to-cell interactions take place
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What signals are involved in cell-to-cell interactions
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Where do effector cells go and how do they get there1
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Read Qi er al 2014
spatiotemporal basis of innate and adaptive immunity in secondary lymphoid tissue
also rewatch the lecture videos
Intravital microscopy
microscopy technique used to observe biological systems in vivo
real time analysis of cell cell interactions
How do lymphocytes exit the blood, and enter the lymphnodes
via HEV = hihg-endothelial venules
HEVs express ligands for L-selectin adhesion molecules
L-selectin is expressed on naive lymphocytes
contact allows the cells to slow down and roll along the vessel walls
further interactions with other adhesion molecules stop the cells and allow them to squeeze through the junctions between the cells
CCR7
is essential for T cell homing to the lymph nodes
S1PR1
sensitivity to S1PR1 recruits T cells back to circulation
HEV
HIgh endothelial venule
T cell - DC interactions under homeostatic conditions
during their meandering migration through the lymph node, T cells have several dynamic interactions with DCs
CD will interact with over 5000 t cells. hr
Lymphocyte migration along fibroblast reticular cells (FRCs)
lymphocytes are guided in their lymph node migration by a 3D network consisting of FRCs on which DCs also reside, thus promoting T cell-DC interactions
FRC network surrounds the HEVs and naive T cell exit from HEVs through openings directly onto the FRC-DC network
HEVs also accommodates newly arriving migratory DCs from peripheral sites
Four key steps of immune cell extravasation from the vasculature into tissues
Rolling
activation
arrest/adhesion
transmigration
Naive lymphocytes are activated in the secondary lymphoid tissue
- > inflammatory chemokines guide T cell migration in the lymph node
- > DCs are essential for the activaiton of naive T cells
- > Requirement of CD4+ T cells in effective memory CD8+ T cell priming
roles of cognate antigen during CD4+ T cells effective memory priming of CD8+ T cells
CD8+ T cells show changes in their migrational pattern in the presence of antigen specific CD4+ T cells interacting with stimulatory DCs
CD8+ T cells migrated more rapidly towards DCs associated with an antigen-specific CD4+ T cell, interacitng with these relevant DCs five to eight times more often than with equidistant irrelevant DCs
CD8+ T cell priming
CD8 DC interactions
DC T cell interactions can last several hours
Phases:
1) Active migration
2) Stable T cell-DC interaction (3-4hrs) = secretion of IL-2 and cytokines
3) T cells resume migratory behaviour, and contine to have short interactions with DCs
CCR5
CCR5 guides naive CD8+ T cells to DCs
T cell receptors
Classical vs non-classical T cells
ab T cells (classical)
gd T cells
ab T cells
TcR heterodimer with an a and b chain
a chain similar in structure to antibody light chain
b chain similar in structure to the antibody heavy chain
classical t cells
CD4+ Th cells = MHCII peptide recognition, immunomodulatory
CD8+ cyt T cells = MHCI peptide recogniton
NKT cells = CD1d lipid recognition, limited variable and J region usage
yd T cells
TcR heterodimer with a g and a d chain
g chain similar in structure to the antibody light chain
d chain similar in structure to the anitbody heavy chain
intraepithelial lymphocytes (IELs)
cytotoxic functions
immunomodulatory functions
abTcR vs gD TcR MHC interactions
ab TcR can only bind MHC or CD1 molecules in the case of NK-Tcells
gd TcR interactions can involve T22 (a non-classical MHC), EPR (a stress protein) or heat shock proteins
= alternate ligands
gd TcR does not required MHC presentation of peptide epitopes, although some recognize MHC class Ib molecules
RAG1/RAG2
recombination is dependeent on these enzymes
shuffled VDJ regions???
variable, diversity and joing/junctional
VDJ rearrangement is essential for TcR diversity
somatic gene reconbinaiton of VDJ gene segments for the b chain
somatic gene recombination of the VJ regions for the a chain
VDJ recombination is the process by which T cells and B cells randomly assemble different gene segments – known as variable (V), diversity (D) and joining (J) genes – in order to generate unique receptors (known as antigen receptors) that can collectively recognize many different types of molecule.
CDR regions
Complementarity-determining regions (CDRs) are part of the variable chains in immunoglobulins (antibodies) and T cell receptors, generated by B-cells and T-cells respectively, where these molecules bind to their specific antigen. A set of CDRs constitutes a paratope. As the most variable parts of the molecules, CDRs are crucial to the diversity of antigen specificities generated by lymphocytes.
MHC-TcR interactions influence specificity of T cell response
topology of peptide- MHC I complexes influences TcR repertoire diversity
Type 1 TcR bias
responding T cell use the same variable regions, but differ in terms of CDR3 or J regiosn
Type 2 TcR bias
responding T cells use the same varable region and a conserved motif in the CDR3 regiosn
Type 3 TcR bias
responding T cell use the same TcR a or b chain or both
Above and beyond cellular and molecular parameters, can you discuss space, movement and time in the context of T cell-DC interactions
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What is intravital microscopy and how has it changed our understanding of immunology
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Make a table discussing 6 differences and similarities between ab and gd T cells
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explain how IG gene recombination contributes to TcR diversity, give an example
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Diverse TcR allows CD4s, CD8s NK and gdT cell to all exist and target different MHC (classical or non-classical or lack thereof)???
What enzymes are responsible for VDJ recombinaiton of TcR
RAG1/RAG2
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