15. Why is the reaction to someone else's plate so violent? · Prof. Kwon's TCR-HLA and CD4/CD8, First Steps

Organ transplantation runs into one wall before any other. Put someone else's tissue in, and the recipient's T cells come at it immediately and very hard.

Put a number on how hard and it stops making sense.

A normal foreign antigen

T cells responding to that fragment: one in 100,000 to a million. On first encounter they have to expand for days before you can see them at all.

Someone else's HLA

Responding T cells: 1 to 10%. One to ten in every hundred. Visible from the start, with no expansion needed.

Ten thousand to a hundred thousand times — this gap is called alloreactivity

These figures come from the literature; this course did not measure them. But they sit right in the middle of the argument lesson 4 could not finish.

The explanations fork in two

🍱

Because there are so many

A single unfamiliar plate carries the whole of that cell's self peptide repertoire. To me, every one of those combinations is new. Not one unfamiliar pMHC but thousands.

🧱

Because the density is high

A normal antigen sits on a cell surface at tens to hundreds of copies. An unfamiliar plate is the entire surface. Even a weak TCR clears the threshold.

🎯

And the germline

If lesson 4's bias model is right, a TCR is born looking at any MHC. On a plate the thymus never screened against, there is nothing to catch it.

The three are not exclusive; all of them happen at once. But if the third is true, alloreactivity is not a mistake by the immune system — it is a side effect of the design.

'An unfamiliar plate' is not one unfamiliar antigen but thousands of them.

Python Runs in your browser

# The skeleton of the 'so many of them' explanation — this is a toy calculation
# A cell displays on the order of 10,000 distinct self peptides on class I.
self_pep = 10000

print(f"{'situation':<34}{'unfamiliar pMHC to me':>24}")
print("-" * 58)
print(f"{'my plate + one foreign fragment':<34}{1:>24,}")
print(f"{'a foreign plate + all my fragments':<34}{self_pep:>24,}")
print()
print(f"{self_pep:,}-fold.")
print("That matches the order of magnitude in the literature, 10,000 to 100,000.")
print("This is a calculation about orders of magnitude, not an exact value.")

The picture from lesson 8 comes straight back. The polymorphism is where a TCR touches.

Python Runs in your browser

# But where on the plate is the difference? This part we really do count.
import thla

h = thla.hla("A")
print("HLA-A · which domain holds the positions that differ between people")
print("(counting positions where the commonest amino acid is under 99%)")
print()
for dom in ["α1", "α2", "α3"]:
    s = h[h["domain"] == dom]
    var = int((s["top_frac"] < 0.99).sum())
    bar = "█" * max(1, int(40 * var / len(s)))
    print(f"   {dom}  positions {len(s):>3}   differing {var:>3}  {bar}")
print()
print("α1 and α2 are the groove; α3 is the platform CD8 grabs (lesson 9).")
print("What is unfamiliar is almost all groove - the very face a TCR reads.")

Change how many groove positions differ and how many unfamiliar fragments there are. Watch the responding fraction move.

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What this number does in the clinic

Setting	Who attacks whom	Its name
Kidney, liver, heart transplant	recipient T cells → the transplanted organ	rejection
Haematopoietic stem cell transplant	donor T cells → the recipient's body	graft-versus-host disease (GVHD)
Haematopoietic stem cell transplant	donor T cells → residual leukaemia cells	graft-versus-leukaemia (GVL)

The last row matters. The same reaction is both a disease and a treatment. Abolish GVHD entirely and leukaemia relapse goes up. So the clinic does not try to remove this reaction; it tries to tune it.

Matching HLA comes from here. In stem cell transplantation you usually match HLA-A, B, C and DRB1, two copies each — eight positions. That is the number behind "8/8".

🤔 Check yourself

Which of these is NOT a reason alloreactivity is so much stronger than a normal foreign antigen response?

🤔 Check yourself

In HLA-A, which domain holds most of the positions that differ between people?

🤔 Check yourself

What goes wrong if GVHD is abolished completely in a stem cell transplant?