11. It is weak — ten thousand times weaker than an antibody · Prof. Kwon's TCR-HLA and CD4/CD8, First Steps

The first people to measure TCR-pMHC binding strength did not believe the result.

K_D = 1 to 100 micromolar

Antibody-antigen binding on the same scale is nanomolar, and the good ones are picomolar. Smaller means tighter. A TCR binds a thousand to a million times more weakly than an antibody.

The receptor that makes the body's most precise judgement binds the most loosely. That is not a failure. It is the design.

Coreceptors are weaker still than the TCR — CD4 is nearly millimolar.

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# Binding strengths taken from the literature — not measured by us
import thla

print(thla.facts()["cited_note_en"])
print()
t = thla.kd_table()
for _, r in t.iterrows():
    print(f"   {r['pair_en']:<24}{r['lo']:>8.4g} ~ {r['hi']:>8.4g} uM")

And yet a T cell without CD4 does not respond. Something is missing from this picture.

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# At these strengths, what fraction is actually bound
import thla

conc = 1.0        # micromolar
print(f"fraction bound when the ligand is at {conc} µM")
for name, kd in [("antibody (KD 0.001 uM)", 0.001), ("strong TCR (1 uM)", 1.0),
                 ("typical TCR (10 uM)", 10.0), ("CD8 (150 uM)", 150.0),
                 ("CD4 (1000 uM)", 1000.0)]:
    occ = conc / (conc + kd)
    print(f"   {name:<24}{100*occ:>7.2f}%")
print()
print("The antibody is nearly all bound; CD4 is essentially not bound at all.")

Change the binding strength and the ligand concentration. Antibodies and TCRs live in different worlds.

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Why weak is an advantage — two reasons

🔁

One fragment wakes many

An infected cell may carry only a handful of copies of the fragment. If a TCR clamps down and never lets go, that fragment triggers exactly one TCR. Letting go quickly moves it to the next one. This is called serial triggering.

⚖️

It separates self from other

A receptor that binds hard also binds things that merely resemble its target — and self peptides mostly resemble pathogen peptides. Binding weakly is what lets you measure the difference in time — lesson 12.

A cytotoxic T cell is thought to be able to kill a target carrying only a countable handful of copies of a fragment. Weak binding is what makes that possible.

🤔 Check yourself

What does TCR-pMHC binding being far weaker than antibody-antigen most accurately mean?

🤔 Check yourself

The solution calculation says CD4 barely binds. Why is it needed anyway?

🤔 Check yourself

What does 'serial triggering' mean?