9. 【Lab】 The seven residues a coreceptor grabs · Prof. Kwon's TCR-HLA and CD4/CD8, First Steps

Last lesson concluded: the polymorphism is in the groove. So what about the patch the coreceptor grabs?

This one is predictable. CD8 has to grip everybody's class I. It cannot afford to differ between people, so that patch had better be conserved.

How conserved? Let us count.

At position 223, D is shared by 99.93% of the 5,839 HLA-A alleles.

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# The loop CD8 grabs — what fraction carries the same amino acid at each position
import thla

lo, hi = thla.CD8_LOOP
for gene in ["A", "B", "C"]:
    d = thla.loop(gene)
    n = thla.facts()["hla_n"][gene]
    print(f"HLA-{gene}  (over {n:,} full-length alleles)")
    for _, r in d.iterrows():
        print(f"   pos {int(r['pos']):>4}  {r['top_aa']}  {100*r['top_frac']:>7.2f}% identical"
              f"   {int(r['n_aa'])} amino acids seen")
    print()

DQTQDTE. These seven letters are the most surprising result in this course.

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# The loop sequence of three genes, side by side
import thla

lo, hi = thla.CD8_LOOP
for gene in ["A", "B", "C", "E"]:
    seq = "".join(thla.loop(gene)["top_aa"])
    print(f"   HLA-{gene:<4} {lo}-{hi}   {'  '.join(seq)}")
print()
print("A, B and C are different genes. Their grooves look nothing alike.")
print("Yet the patch CD8 grabs is the same seven letters.")

Fifteen to thirty-one times apart — inside the same molecule.

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# Measure groove and loop with the same ruler
import thla

for gene in ["A", "B", "C"]:
    e = thla.domain_entropy(gene)
    groove = (e.loc["α1", "mean"] + e.loc["α2", "mean"]) / 2
    d = thla.loop(gene)
    ring = d["entropy"].mean()
    print(f"HLA-{gene}   groove (α1·α2) {groove:.4f}   CD8 loop {ring:.4f}"
          f"   ratio {groove/ring:>5.0f}x")

Measure groove and loop with the same ruler. Change the plate and the loop does not move.

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What about class II — here the story shifts a little

Run the same calculation on the patch CD4 grabs (β2 domain, 134-148). The result is not as clean as class I. We report that as it is.

A ratio of 2.5 to 6.4 — a different story from class I's 15 to 31.

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# How conserved is the patch CD4 grabs
import thla

lo, hi = thla.CD4_LOOP
for gene in ["DRB1", "DQB1", "DPB1"]:
    e = thla.domain_entropy(gene)
    d = thla.loop(gene)
    seq = "".join(d["top_aa"])
    print(f"HLA-{gene:<6} β1 {e.loc['β1','mean']:.4f}   "
          f"CD4 site {d['entropy'].mean():.4f}   ratio {e.loc['β1','mean']/d['entropy'].mean():>4.1f}x")
    print(f"          {lo}-{hi}  {seq}")

What this result means

MHC restriction happens in the groove only

Take your CD8 T cell and put it in front of somebody else's cell, and CD8 binds without any trouble — the platform is the same.

Every rejection happens in the groove: the TCR meets an unfamiliar groove and either reacts strangely or fails to read it at all. That is the structural root of alloreactivity in lesson 15.

🤔 Check yourself

What does it mean that positions 223-229 are identical in HLA-A, B and C?

🤔 Check yourself

What conclusion does this course draw about the CD4-binding β2 site?

🤔 Check yourself

What limitation of this entropy calculation does the course flag?