IMMUNOLOGY Bios 328 a textbook-based study of immunology

IMMUNOLOGY Bios 328 a textbook-based study of immunology

IMMUNOLOGY Bios 328 a textbook-based study of immunology Spring 2003 http://www.lehigh.edu/~sk08/Courses/Bios328/mainpage.htm TCRs 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 TCRs. A T-cell receptor is a heterodimer. A heterodimer is made from two different protomers.

T-cell heterodimers are either: (alphaalphabeta) (alphagammadelta) There are two types of T-cells: TH & TC. Can they have the same TCR? (alphaYes.) So, TH & TC must be distinguished some other way.

(alphaMore about that later.) A T-cell receptor is a heterodimer. A heterodimer is made from two different protomers. T-cell heterodimers are either: (alphaalphabeta) (alphagammadelta) Either is an important word in that previous statement.

There must be a genetic mechanism for having one heterodimer and excluding the other. (alphaMore about that later, too!) What do T-cell receptors do? Two things: Respond to MHC Respond to Ag

More exactly, they see one histotope and many, many types of processed antigens. Implication: There is some constancy (alphacareful here) and huge amounts of variety, too. A genetic mechanism is needed. OK. Enough premises! Lets look at some pictures! Hmmm

Not very pretty but very informative. Whats being said? Consider all the symbolic notations. What do the symbolic notations convey?

Ig is bivalent. TCR is monovalent. Lots of immunoglobulin folds (alphadomains) present. variable component constant component Tm component. Short CTs

So, we have these complicated proteins i.e., these complicated gene products What is the genetic organization of the loci for these products? So, lets look at the protein again Two views will be informative First, this already seen

and, this. The previous slide implies rearrangements Lets take a look: Theres something odd in this slide. Did you see it?

Lets look at this image and put on our thinking caps 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?

Theyre still there. Why are they not expressed? How are the questions in the previous slide answered? 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 (alphaassuring 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 gammadelta heterodimers are produced.

TCR DNA templates (alphaand primary transcripts) for the alpha, beta, gamma, and delta chains have nucleotide sequences specifying variable components (alphaV, [D], and J) and constant components (alphaconstant domain, connecting sequence, transmembrane region, and cytoplasmic tail.) Sounds familiar Lets take a look: Diversity (alphaand constancy)

TCRs 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. (alphaThere is no somatic hypermutation.) So, there is a huge variety in CDR3; CDR1 and

CDR2 obtain their variety from the selection of V segments.

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