A watchdog that yawns and turns away instead of barking at an intruder is a bad guard. That is roughly how CD8+ T cells behave in people with type 2 diabetes. These cells are professional killers: they patrol the body, find infected or cancerous cells, and destroy them. But in diabetes, something breaks in the recognition system itself, and the watchdogs stop recognizing the enemy.
Scientists compared T cells from healthy older people and from patients with diabetes. It turned out that in diabetes, memory cells become too "adult" — they are called TEMRA. They have shorter protective caps on the ends of their chromosomes, less diversity in the receptors that catch the enemy, and on top of that they accumulate in the spleen, as if they cannot get out on patrol. But most importantly: the surface of these cells had fewer of three sensors — KLRG1, NKG2D, and NKG2A. These sensors help a T cell figure out that the cell in front of it is sick and launch an attack. Without them, the dog goes blind.
Researchers tested this hunch. They took healthy T cells, treated them with TGFβ1, and saw the same changes: the sensors disappeared from the surface, and the cells stopped releasing their toxic granules properly. What's more, the cells had plenty of granules, but the release just didn't fire. It's as if the dog has a mouth full of teeth but can't bite because it doesn't understand where to bite.
To figure out where the cells go, they labeled them with radioactive zirconium-89 and injected them into mice. It turned out that T cells from people with diabetes get stuck in the spleen more than cells from healthy people. The spleen is a barracks for immune cells, but a good guard needs to go out into the streets, not sit in the barracks.
It used to be thought that the immune system in diabetes simply ages faster. Now it's clear that the disease doesn't accelerate aging but creates a special type of cell: sluggish watchmen that have lost their sense of smell and sight. Can they be made vigilant again? If TGFβ1 is removed or the delivery of sensors to the surface is restored, the cells might start barking again. But for now that's just a hope: simply reducing inflammation may not be enough, because damage has already accumulated inside the cell.
In patients with diabetes, memory T cells have shorter telomeres but more telomerase (TERT) than those of healthy peers. This looks paradoxical: the cell tries to compensate for wear and tear but cannot stop aging.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.