Mystery Rays from Outer Space

There are maybe 10¹¹ naive T cells in a human body. How many of those T cells can recognize any particular antigen?

About twenty.

OKTHXBYE!

… Well, if you want a little more expansion of that (and all the weasel words that go along with it) …

T cells have to recognize the entire universe of all possible pathogens, and they generally manage to do so; it’s not often that people are infected with a pathogen that simply doesn’t elicit a T cell response. On the other hand, for all the possible antigens present in Generic Joe Pathogen, T cells typically only recognize a handful of them; you don’t see a massive upwelling of T cells that recognize every possible epitope in the pathogen.

Floating around your body, there are somewhere between, let’s say, 10⁸ (if you’re a mouse) and 10¹¹ (if you’re a human) naive T cells. ¹ It’s that population that must be prepared to take on our hypothetical universe of pathogens. In other words, the largest number of antigens you could possibly recognize is 10⁸ – 10¹¹, if each naive T cell recognized a distinct antigen.

Is there redundancy among T cell specificities? If so, how many T cells typically recognize an individual antigen? And therefore, how may distinct antigens can your body detect?

When a T cell is allowed to exit the thymus, where it matures, it has a T cell receptor (TcR). That TcR is what interacts with, say, a viral antigen, and what allows the T cell to respond in its specific and (hopefully) appropriate way. TcRs are formed by genomic rearrangement, shuffling a moderate handful of possible segments to form, by combinatorial multiplication, a very large number of possible sequences. (If you want a mechanism, see any introductory immunology text, or Wikipedia. ) How large is a “very large number of possible sequences”? In theory, it could be as many as 10¹⁵ different TcRs², but in practice it’s probably more like 10⁸.³ (And that’s 10⁸ possible clones — precise TcR sequences. There’s more than one way to skin a virus: TcRs with different sequences can recognize the same epitope.)

At any rate, it seems TcR diversity is, very roughly, on the same order of magnitude as naive T cell abundance; or perhaps a little less. We would expect maybe up to a thousand, maybe a few more, maybe a lot fewer, T cells per epitope. That doesn’t help us all that much with the question; we’re left with having to measure directly.

Directly measuring the frequency of naive T cells is, as you can imagine, very difficult. You’re looking for an event with a frequency of at most 1/100,000, with the positives spread out among an entire mouse (or an entire human). Several groups have tried, and have published their results to widespread raised eyebrows. Just recently, Marc Jenkins’ group has taken another run at the problem,⁴ and this time there’s more of the thoughtful nodding and less of the skeptical frowns.

The paper is almost entirely technical, so I won’t go into any details. Suffice it to say that they show fairly convincingly that they are counting what they say they are, and that they’re not missing many of them. (Mark Davis has a commentary⁵ on the paper, in which he points out some caveats and cautions — though I agree with his points, I don’t think they’re likely to throw the estimates way out of whack. For now, let’s accept the numbers but mentally add some grey fuzz to the upper side.)

Here’s what they found. They looked at three T cell epitopes. One yields a large, one a medium, and the other yields a smallish T cell response when you infect with the appropriate conditions. For the “large” epitope, they estimated their mice contained 190 naive T cells specific for it; the “medium”, about 20; the “small”, about 16.

Sixteen T cells, swimming about among the vast pool of irrelevant T cells and distributed randomly through the body’s lymphoid tissue, are capable of generating an immune response that, in less than 6 days, will expel invading pathogens.

The next cool thing was the link to the ultimate T cell response. Over the first 6 days of an immune response, the “large” epitope response went from around 190 T cells to around 80,000; the medium, from 20 to 5000; the small, from 16 to 3000 cells. (The figure at right shows the cell counts for each T cell group, over time. Note that it’s a log Y axis.) The expansion is quite similar for all three epitopes: 400-fold, 250-fold, and 200-fold. Here I’m going to quibble with the Moon et al interpretation. They call these all “about 300” (fair enough, I suppose) and argue that each ultimate response was proportional to the number of naive cells. While I can see that for the biggest response, I’m skeptical that 20 is actually different from 16 — though the error bars aren’t spelled out, they clearly overlap a lot — and I’m also skeptical that 400-fold is the same as 200-fold. Also, of course, this is just three epitopes. I think it’s equally likely that while the size of the naive precursor pool is one factor, you can also get different T cell responses out of the same number of precursors, for any of a variety of reasons.

(Of course, this is a part of the immunodominance equation that I’ve touched on before.)

Still, it’s an interesting suggestion, and their data certainly are suggestive. I’m sure there will be more epitopes examined by this technique over the next little while, so we’ll see how well it holds up.

Incidentally, it’s been stated (I don’t know the data well enough to judge how accurately) that after naive T cell clones⁶ leave the thymus, they divide a little bit — just ticking over, compared to the vast expansion after they meet their antigen, but enough to expand each clone up to maybe 10-fold or so. If so, the two smaller naive populations here may have originated with just a handful of T cell clones. Jenkins’ group actually looked at TcR sequences, and their findings are roughly consistent with this idea. Certainly these small pools had a very limited number of TcR clones within them, and the larger pool had a lot more T cell clones, but there wasn’t enough material to tweeze it down much finer than that.

1. “Naive” means they haven’t encountered their cognate antigen yet. After they encounter antigen, they’ll typically divide and multiply immensely.[↩]
2. T-cell antigen receptor genes and T-cell recognition. Davis, M. M., P. J. Bjorkman. 1988. Nature 334:395. [↩]
3. T. P. Arstila et al., Science 286, 958 (1999).[↩]
4. Naive CD4(+) T Cell Frequency Varies for Different Epitopes and Predicts Repertoire Diversity and Response Magnitude. Moon JJ, Chu HH, Pepper M, McSorley SJ, Jameson SC, Kedl RM, Jenkins MK. Immunity. 2007 Aug;27(2):203-13. [↩]
5. The αβ T Cell Repertoire Comes into Focus. Davis MM. Immunity. 2007 Aug;27(2):179-80. [↩]
6. A clone being a T cell with a specific TcR sequence[↩]