Germline bias versus thymic selection · an argument that is not over
Why do receptors built at random point uniformly at MHC? There are two answers, and both have evidence.
Something here does not add up.
A TCR is assembled by V(D)J recombination almost at random. Yet the
things that come out all look at MHC. If you made 108 random
locks and every one of them fitted the same key, the making was not random.
Who set the direction — the genes, or the thymus?
Answer ① it is already written in the germline
Philippa Marrack and John Kappler collected hundreds of TCR-MHC structures
and counted which residue touches which residue, across all of them.
A pattern came out. A residue at a particular CDR2 position of a particular
TRBV gene paired with a particular position on the MHC α1 helix, again and
again — across different people, different antigens, different structures.
They called it a codon: the claim that a hand for touching MHC
has been written into V genes for hundreds of millions of years.
Answer ② the thymus merely picked those out
The evidence on the other side is more startling.
Alfred Singer's lab made mice whose thymus had no Lck. Normally CD4 and
CD8 have to deliver Lck for positive selection to happen; without it, T cells
that read MHC do not get selected.
The T cells that emerged from those mice recognised things that were
not MHC — ordinary cell-surface proteins like CD155, seen whole,
the way an antibody sees them.
Which is to say: a TCR could always have seen anything, and the thymus is
what leaves only the MHC-readers behind.
Give each model weight and watch which predictions come apart.
Loading…
Under randomness one gene should be around 2%. It is not.
PythonRuns in your browser
Where it stands — a bit of both
Explained by germline bias
Docking polarity is nearly constant.
Particular V gene-MHC allele pairs recur.
Immature cells lean toward MHC before they ever meet the thymus.
Explained only by thymic selection
An Lck-free thymus yields TCRs that read things that are not MHC.
Structures with reversed docking polarity genuinely exist.
The same TCR can sit at different angles on different MHC molecules.
The honest summary: the germline tilts it and the thymus finishes it.
Nobody yet knows the split.
🤔 Check yourself
What did the Lck-free thymus experiment show?
Answer With no coreceptor to deliver Lck, the MHC-biased selection never bites — and TCRs that read whole proteins the way an antibody does survive.
🤔 Check yourself
What is the evidence behind Marrack and Kappler's 'codon' claim?
Answer Pooling structures and counting contacts turned up the same pairings over and over. Their argument is that the repetition is too regular to be chance.
🤔 Check yourself
What position does this course take on the argument?
Answer Not pretending a question is settled is a rule of this site. Lesson 20 grades 'what we can say and what we cannot', line by line.
