Phosphorylation of Cell Surface Receptors: A Mechanism for ...
TCR’s… T-cell receptors… Some fundamentals… T-cells have T-cell receptors. Nota bene: The...
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Transcript of TCR’s… T-cell receptors… Some fundamentals… T-cells have T-cell receptors. Nota bene: The...
![Page 1: TCR’s… T-cell receptors… Some fundamentals… T-cells have T-cell receptors. Nota bene: The previous statement is ambiguous. One T-cell has one type of.](https://reader038.fdocuments.us/reader038/viewer/2022110401/56649dff5503460f94ae84b9/html5/thumbnails/1.jpg)
IMMUNOLOGY
Bios 328a textbook-based study of immunologySpring 2003
http://www.lehigh.edu/~sk08/Courses/Bios328/mainpage.htm
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TCR’s… T-cell receptors…Some fundamentals…
T-cells have T-cell receptors.
Nota bene: The previous statement is ambiguous.
One T-cell has one type of TCR.
One T-cell has one TCR with a wholly unique specificity.
One T-cell has as many as 100,000 identical TCR’s.
![Page 3: TCR’s… T-cell receptors… Some fundamentals… T-cells have T-cell receptors. Nota bene: The previous statement is ambiguous. One T-cell has one type of.](https://reader038.fdocuments.us/reader038/viewer/2022110401/56649dff5503460f94ae84b9/html5/thumbnails/3.jpg)
A T-cell receptor is a heterodimer.
A heterodimer is made from two different protomers.
T-cell heterodimers are either: (alpha•beta) (gamma•delta)
There are two types of T-cells: TH & TC. Can they have the same TCR? (Yes.)
So, TH & TC must be distinguished some other way. (More about that later.)
![Page 4: TCR’s… T-cell receptors… Some fundamentals… T-cells have T-cell receptors. Nota bene: The previous statement is ambiguous. One T-cell has one type of.](https://reader038.fdocuments.us/reader038/viewer/2022110401/56649dff5503460f94ae84b9/html5/thumbnails/4.jpg)
A T-cell receptor is a heterodimer.
A heterodimer is made from two different protomers.
T-cell heterodimers are either: (alpha•beta) (gamma•delta)
Either is an important word in that previous statement.There must be a genetic mechanism for having oneheterodimer and excluding the other. (More about thatlater, too!)
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What do T-cell receptors do?
Two things:Respond to MHCRespond to Ag
More exactly, they see one histotope and many, many types of processed antigens.
Implication: There is some constancy (careful here) and huge amounts of variety, too. A genetic mechanism is needed.
![Page 6: TCR’s… T-cell receptors… Some fundamentals… T-cells have T-cell receptors. Nota bene: The previous statement is ambiguous. One T-cell has one type of.](https://reader038.fdocuments.us/reader038/viewer/2022110401/56649dff5503460f94ae84b9/html5/thumbnails/6.jpg)
OK. Enough premises! Let’s look at some pictures!
Hmmm…
Not very prettybut very infor-mative.
What’s being said?
Consider allthe symbolicnotations.
![Page 7: TCR’s… T-cell receptors… Some fundamentals… T-cells have T-cell receptors. Nota bene: The previous statement is ambiguous. One T-cell has one type of.](https://reader038.fdocuments.us/reader038/viewer/2022110401/56649dff5503460f94ae84b9/html5/thumbnails/7.jpg)
What do the “symbolic notations” convey?Ig is bivalent.
TCR is mono-valent.
Lots of immuno-globulin folds(domains) present. variable component
constant component
Tm component.
Short “CT’s”
![Page 8: TCR’s… T-cell receptors… Some fundamentals… T-cells have T-cell receptors. Nota bene: The previous statement is ambiguous. One T-cell has one type of.](https://reader038.fdocuments.us/reader038/viewer/2022110401/56649dff5503460f94ae84b9/html5/thumbnails/8.jpg)
So, we have these complicated proteins…i.e., these complicated gene products…
What is the genetic organization of the loci for these products?
![Page 9: TCR’s… T-cell receptors… Some fundamentals… T-cells have T-cell receptors. Nota bene: The previous statement is ambiguous. One T-cell has one type of.](https://reader038.fdocuments.us/reader038/viewer/2022110401/56649dff5503460f94ae84b9/html5/thumbnails/9.jpg)
So, let’s look at the protein again…
Two views will be informative…
and, this….
First, this already seen…
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The previous slide implies rearrangements…
Let’s take a look:
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There’s something odd in this slide.
Did you see it?
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Let’s look at this image and put on our thinking caps…
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There are two genetic problems to solve:
How is it that only or are expressed?
How does exclusion of one occur?
After a “V” cassette has been selected,– Downstream cassettes are “deleted”– But what about upstream cassettes?– They’re still there.– Why are they not expressed?
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How are the questions in the previous slide answered?
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There are two genetic problems to solve:Determinants for delta chain are – in mouse – tucked
within the segments for the alpha chain.
If an alpha V segment is fused with an alpha J segment, the delta cassettes are deleted (assuring that delta is not expressed if alpha is expressed.)
If a delta V segment is fused with a delta J segment,
the alpha cassettes are not expressed because they remain too far from the ENHANCER.
Thus, the “embedded” organization of delta within alpha assures that only alpha-beta or gamma-delta heterodimers are produced.
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TCR DNA templates (and primary transcripts) for the alpha, beta, gamma, and delta chains have nucleotide sequences specifying variable components (V, [D], and J) and constant components (constant domain, connecting sequence, transmembrane region, and cytoplasmic tail.)
Sounds familiar…Let’s take a look:
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Diversity (and constancy…)
TCR’s have CDR1, CDR2, and CDR3. The variability in CDR3 comes from
combinations of V-J and V-D-J joining, variable numbers of D segments joining together, junctional flexibility, N-region nucleotide addition, P-nucleotide addition, and combinatorial association of chains.
(There is no somatic hypermutation.) So, there is a huge variety in CDR3; CDR1 and
CDR2 obtain their variety from the selection of V segments.