5. CD4 and CD8 — what exactly do they hold? · Prof. Kwon's TCR-HLA and CD4/CD8, First Steps

Here is the sentence this course is built around.

CD4 and CD8 do not look at the fragment

The TCR looks at the fragment, so changing the fragment makes the TCR let go. A coreceptor is different: it grips the platform at the bottom of the MHC molecule, and that patch stays exactly the same whatever is loaded above.

	CD8	CD4
Plate it grips	Class I (HLA-A·B·C)	Class II (HLA-DR·DQ·DP)
Where exactly	the acidic loop of the α3 domain, 223-229	the β2 domain, 134-148
Shape	αβ dimer (αα also exists in the thymus)	a single chain, four domains
Inside the cell	both carry Lck on the tail (lesson 13)

How this was worked out

In 1990 Salter and Parham built hybrid molecules, swapping a few positions of the HLA-A2 α3 domain for the class II equivalents. CD8 T cells then read those molecules poorly — even though the groove the TCR binds had not been touched at all.

In 1992 Cammarota and König each showed that residues 134-148 of the class II β2 domain are required for CD4 binding. Two neighbouring papers, same year, same journal.

Then in 1997 Gao and Jakobsen solved the CD8αα-HLA-A2 crystal structure. CD8's two arms were clamped around the α3 loop like a pair of tongs.

Three different class I genes, not one letter apart at the CD8 site. Lesson 9 digs into what that means.

Python Runs in your browser

# What sequence is the loop CD8 grips? Pull it straight out of the data.
import thla

for gene in ["A", "B", "C"]:
    d = thla.loop(gene)
    seq = "".join(d["top_aa"])
    lo, hi = thla.CD8_LOOP
    n = thla.facts()["hla_n"][gene]
    print(f"HLA-{gene}  positions {lo}-{hi}  {seq}   (over {n:,} full-length alleles)")
print()
for gene in ["DRB1", "DQB1", "DPB1"]:
    d = thla.loop(gene)
    lo, hi = thla.CD4_LOOP
    print(f"HLA-{gene}  positions {lo}-{hi}  {''.join(d['top_aa'])}")

Attach and detach the coreceptor. What changes falls into three parts.

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A coreceptor does three jobs

🤝

① It holds on

The TCR-pMHC complex lasts longer. This contribution is smaller than you would guess — lesson 11.

🚚

② It delivers an enzyme

It sets the Lck hanging off its tail down right beside the TCR. This is the real job — lesson 13.

🚪

③ It picks a class

CD8 reads only class I, CD4 only class II. The thymus splits the two lineages on it — lesson 14.

🤔 Check yourself

Where does CD8 bind?

🤔 Check yourself

What is the advantage of gripping the platform rather than the groove?

🤔 Check yourself

Where does CD4 bind?