Dicing with Death
Dicing with Death
By Abraham a Sancta Clara and Christoph Weigel, 1764 

Why aren’t our bodies choked with T cells?

Whenever we’re infected with a microbe (which is often, even if we aren’t aware of it) our immune system reacts. As part of the reaction, T cells become activated, and as part of the activation, the T cells replicate, at an incredible rate. We may start off with a few hundred T cells that react with any particular microbe, but within a week each of those will expand between a thousand and a hundred thousand fold, so for each microbe that is carried in on a splinter, or that we breath in, we will develop millions of T cells. After ten or twenty years of this, we should be nothing but a gigantic, rolling ball of T cells.

We’re not a ball of T cells because the T cells die off. After a week, or thereabouts, most of those millions of T cells die: About 95% of them. The remaining 5% or so stick around, as memory cells, but almost all of them are cleared away to make room for the next immune response.

How does that die-off work? How do cells decide if they’re going to die, or survive and become a memory cell? How do they know that the response has been going on long enough? Bits and pieces are already known. For example, there are spontaneously-mutant mice (“lpr” and “gld” mice) that don’t look after the die-off properly (because one of the pathways that’s involved in delivering a “death” signal to the T cells is defective in these mice; they lack Fas and FasL, respectively). The figure on the right is what happens to them. The right-most panel shows a spleen and some lymph nodes from a normal mouse; the left panel shows the same, from an lpr mouse. 1 The grotesquely oversized lymph nodes are crammed with T cells: Normal T cells, in that they’re not cancerous, but there are far too many of them, and these mice die young.

spleen and lymph nodes from an lpr mouseBut in spite of these little snippets of information, “The contraction phase that connects the initial expansion phase with the memory phase has been a black box from which surviving effectors emerge as bona fide long-lived memory cells”.2

Michael Bevan has just published some more data on the T cell contraction phase (at least for one T cell subset, the CD8 T cells).2 He manages to rule out a couple of the major hypotheses as to how contraction works, and his conclusion is that the contraction is part of the overall response program — it’s all predetermined during the brief period, at the beginning of the immune response, where the T cells are activated and set forth onto their journey. They become activated, expand, control infection, and then contract, all based on a hardwired program that kicked on days earlier.

That doesn’t explain, though, why some cells don’t die off and end up becoming memory cells. Bevan basically shrugs; there doesn’t seem to be anything different about the survivors, and he suggests that it’s just chance; that cell division isn’t completely symmetrical, and that some cells end up more equal than others:

Cell death could be the default pathway during contraction and a combination of epigenetic modifications and transcriptional changes could allow a subset of cells to survive and progress to the memory stage.

That’s a little unsatisfying, though “unsatisfying” doesn’t mean “wrong” by any means. It would be a little easier to understand if there were some special signals or some special predetermination that established the proper numbers for memory, and so on, but maybe assymetric division is all there is.

  1. I wish I had noted down where I took this figure from. I’ve been using it in classes for a while now.[]
  2. M. Prlic, M. J. Bevan (2008). Exploring regulatory mechanisms of CD8+ T cell contraction Proceedings of the National Academy of Sciences, 105 (43), 16689-16694 DOI: 10.1073/pnas.0808997105[][]