Immuno-T lymphocytes; genetics of TCRs-T cell activation
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T cells: Key points
1) T cells recognize Ag when __________.
2) T cells recognize ______ Ag.
3)TCRs recognize Ag in association with _____.
4)TCRs are restricted to _____-MHC -
1)bound to the surface of cell
2)Protein
3)MHC
4)self - H-2K and H-2d
- two different mouse class I MHC used to to demonstrate the fact that TCRs are restricted to self-MHC
- Exception to the rule that TCRs are restricted to self-MHC
- Alloreactivity
- Alloreactivity is when TCR recognize foreign MHC. Often times, this is the reason for graft rejection. T-cells recognize foreign MHC as an _________ without a Ag peptide. ~1-10% of T cells can recognize foreign MHC. In this case T cells are not _________
- ALLOANTIGEN/SELF-MHC RESTRICTED
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TCR structure
TCR is a Heterodimer with
ab or gd chains. It is very similar to the Fab portion of the B cell Ab.
Disulfide bonds and membrane anchors hold it together. Similar to B cell Ab there is a hInge region, _______ and const - VARIABLE/CDRs
- ab versus gd T cells
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-ab are the vast majority of CD3+ cells.
-They have much MORE TCR diversity.
-60% ARE CD4+ compared to <1% in gd
-ab are predominantly CD4+ where as gd are mostly CD8+
-CD4+ are restricted to MHC class II & CD8+ are restricted to MHC class I, where as in gd there are no restrictions.
-ab respond to the MHC-Ag peptide complex, whereas gd mostly just respond to phospholipid Ag - In TCR genes the _____ locus is within the _____ locus, while the ______ and ______ loci are on the same chromosome but seperated.
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delta/alpha
beta/gamma -
TCR genes continued
alpha and gamma have a __ and __ (similar to Ig light chain)
beta and delta have a _, _, and _ (similar to Ig H chain) -
V/J
V/D/J -
TCR genes continued
Because the alpha locus is split by delta locus, a
productive rearrangement of ALPHA DELETES THE DELTA LOCUS the purpose of this is? - So that you can’t have both a and d.
- Describe the C region of the TCR in relation to the IgH chains. Why are they different.
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They are much simpler than IgH chains.
They have no different biological activities of TCRs. - TCR gene rearrangement occurs in the _______
- Thymus
- Placement of V & J regions in TCR gene rearrangement is directed by RSS (recombination signal sequences) which consists of a _______-_______-________. Spacer is a _______ sequence.
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HEPTAMER-SPACER-NONAMER
12 OR 23 BP - In TCR gene rearrangement the ______ genes/enzymes are involved in cutting and pasting the V,D, J regions together
- RAG1/RAG2
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TCR gene rearrangement is a sequential process (as with Ig genes) the beta, gamma, and delta chain ____________.
If gamma delta have complete rearrangement first, then it will be a gamma delta T cell
If beta is first, it associates with a _____ -
REARRANGE SIMULTANEOUSLY
PRE-T ALPHA
AB T CELL - Allelic exclusion means
- for a given T cell, only one allele should be expressed at the same time
- Exception for allellic exclusion
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alpha locus not as tightly controlled so we CAN SEE 2 ALPHA ON THE SURFACE WITH THE SAME BETA CHAIN.
Most often, one TCR alpha beta is self-MHC restricted (i.e., functional) - Diverisity of TCR - compare it to Ig diversity and explain.
- more diversity in TCR than in Ig(even though fewer V region genes) because there is a HIGHER NUMBER OF J REGIONS.
- Adding to the diversity of TCR is the fact that we can have alternative joining of ______ regions on the beta chain.
- D regions
- Diversity of T cells is due to
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1) Junctional flexibility
2) P nucleotides
(palindromic base additions)
3) N nucleotides (TDT enzyme addition)
these three thought to generate ~1013 possibilities (~107 for Abs) - T cells are different from B cells in that you get NO SOMATIC HYPERMUTATION. True or False
- True
- Explain how diversity in TCR depends on contact with MHC
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There are fewer V region genes because have to contact limited number of MHC molecules. Specifically,
CDR1 and CDR2 INTERACT DIRECTLY WITH MHC so they are not very diverse.
There are higher number of J regions because these are the areas that have higher contact with Ag peptides (CDR3). - TCR complex
- TCR and CD3 complex
- Describe CD3
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- INVARIANT CHAINS
- MOSTLY INTRACELLULAR
- intramembrane is NEGATIVELY CHARGED (to interact with positive charges of TCR)
-it has a SIGNALLING FUNCTION which utilizes ITAMs (immunoreceptor tryosine-based activation motifs)
- there are 3 ITAMS in the zeta homodimer and one on other CD3 polypeptides
-When binding Ag, conformational changes send signals to CD3 which then starts signaling cascade. - T cell accessory molecules (co-receptors)
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CD4 contacts beta2 domain of class II
CD8 with alpha3 domain of class I - importance of coreceptors
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Increase avidity of TCR with MHC and are needed for optimal signaling
E.g.,
100 TCR/Ag/MHC for activating T cell WITH CO-RECEPTOR
10,000 TCR/Ag/MHC for activating T cell WITHOUT CO-RECEPTOR(rarely would happen - Adhesion molecues
- help hold T h/T c and Ag presenting cell/ Target cell together
- 2nd signal in T cells
- CD28 cell(on T helpser cell)binds with B7 (on presenting cell)
- T cell maturation/differentiation
- progenitor T cells originate in bone marrow and move to thymus to be “educatedâ€
- lack of thymus showed ________
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T cell defects
e.g., DiGeorge Syndrome -
T cell maturation/differentiation (cont.)
Earliest T cells express CD2 and are _______ or CD4-/CD8-
These cells go on to become either ab or gd T cells
Gene rearrangement begins in thymus - DOUBLE NEGATIVE
- Describe the Pre-T cell receptor stage of T cell maturation/differentiation
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You have CD3, beta chain and pre-Talpha.
There is no CD4/CD8 expressed (double negative)
This stage is important in signaling to continue development (start alpha chain rearrangement) -
T cell maturation/differentiation (cont.)
Double negatives become ________(CD4+/CD8+)
These cells proliferate before alpha chain gene rearrangement. This increases diversity by putting same beta chains with different alpha. - DOUBLE POSITIVES
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T cell maturation/differentiation (cont.)
After successful ab gene rearrangement, cells “tested†for binding
self reactive cells __________ (~98% of all T cells. Surviving cells become __________. - DIE VIA APOPTOSIS/SINGLE POSITIVES
- Thymic selection consists of what two selection processes
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-positive selection
-negative selection - describe positive selection
- select T cells that can interact with self-MHC
- describe negative selection
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T cells with high affinity for self-MHC alone &
T cells reactive to self-peptides die via apoptosis (cells not reacting are selected) - which cells do the selecting
- thymic stromal cells because they have high levels of MHC I & II
- How long does the selection process take
- ~3 weeks
- After which stage of selection does cell become CD4+ or CD8+
- After negative selection
- two-signal hypothesis
- In order to be activated, T cells need two signals
- What are the 2 signals for T cells
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Signal #1: TCR – Ag/MHC
Signal #2: CD28 / B7 - What is the significance of CTLA-4
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It is a 2nd signal that binds B7 with higher affinity than CD28 (on activated T cells)
It may send “suppression†signal - What happens to T cells without 2 signals?
- T cells become anergic or apoptotic
- What are superantigens?
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They bind to a particular V Beta family and result in activation of a large population of T cells
There is a cytokine release.
Pathology is(inflammation, systemic cause shock)
apoptosis/anergy of stimulated T cells
e.g., are staphylococcal enterotoxins, Toxic-shock syndrome toxin, exfoliative-dermatitis toxin, streptococcal pyrogenic exotoxins, etc. - T cell subsets
- ab and gd and NK1-T cells
- gd
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0.5-10% of all T cells
Do not recirculate
Express limited diversity
Skin/intestines - NK1-T cells
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have rearranged TCRs (ab)
bind to CD1 MOLECULES(NOT CLASSICAL MHC) and lipids (Ag)
effector function similar to NK cells (cytotoxic)
secrete cytokines to attract Th cells
may function as a rapid response to invader (don’t need Ag processing of Ag - ab T cell subsets
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CD4 (Th cells and Td cells)
& CD8 (Tc and Ts cells) - Th0
- precursor helper cell (IL-2, IL-4)
- Th1
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IL-2, IFNg, and TNF-b (CMI)
(KNOW) - Th2
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IL-4, IL-5, IL-6, and IL-10 (Ab)
(KNOW) - Delayed type hypersensitive T cells (Tdth)
- CD4 cells that stimulate inflammation
- CD8 (Tc and Ts cells)
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CTLs
suppressor T cells