Mouse polyomavirus
Mouse polyomavirus

When we talk about anti-viral T cells, we’re usually talking about cytotoxic T lymphocytes (CTL) that recognize a peptide in association with class I major histocompatibility complexes (MHC class I). MHC class I is extremely polymorphic; there are many hundreds of different MHC class I alleles.

At any rate, that’s true for the classical MHC class I genes. But as well as classical MHC class I, there are also (you’ll never guess) non-classical MHC class I genes. Lots of them. For the most part we don’t really know quite what they do. Typically they’re not very polymorphic, compared to classical class I alleles. Since the major hypotheses explaining which there are so many classical MHC class I alleles involve protection against pathogens, this might hint that non-classical MHC class I don’t behave like classicals — either they don’t protect against pathogens at all, or they do so in a very different way.

Both of these possibilities are true for various non-classicals. For example, some of the non-classical MHC class I genes act as ligands for natural killer (NK) cells, which do recognize pathogens but do so in a very different manner than do CTL. Other non-classicals seem to have little to do with pathogen recognition — there are iron-binding molecules, neuronal molecules, and so on.

But a paper from Aron Lukacher’s lab1 suggests that at least some non-classical MHC class I genes can act much like the classical genes, which has interesting implications for anti-viral vaccines.

There are mice that have no classical MHC class I genes at all. (Hidde Ploegh’s lab generated them, by crossing mice lacking the H-2K MHC class I gene with those lacking the H-2D MHC class I gene. Since these genes are side by side, the frequency of crossing-over is very low, and Ploegh got the mice by pure brute force, examining thousands of mice to find the single mouse that had crossed over appropriately to generate a double knockout. I have always felt a mixture of admiration and sympathy for the post-doc assigned that project.) These mice actually do reasonably well as far as controlling viruses — the immune system is highly redundant, and there are many antiviral systems in play – so it wasn’t a huge surprise to find that the classical MHC class I-less mice could control infection with polyomavirus quite well.

What was a surprise was that eliminating CD8 T cells also eliminated polyomavirus control. 2 If there’s no classical MHC class I, what could the CD8 T cells be recognizing? The answer turned out to be, non-classical MHC class I. 3 WIth a bit more mapping, it seems that the CD8 T cells were recognizing a non-classical MHC class I gene called “Q9” (catchy, eh?).

Qa-2 non-classical MHC class IQ9 is a member of the Qa-2 family, which I have always believed were involved in natural killer cell recognition,4 although in retrospect I see that there’s evidence that CD8 T cells can recognize them.5  That’s a picture of Qa-2 off to the right (click for a larger version), and there are more images of it in my previous post comparing the different types of MHC.

What’s more, the CD8 cells recognize a really pretty conventional epitope. Classical MHC class I alleles present peptides that are around 9 amino acids long, while various non-classical proteins present anything from glycolipids to nothing at all. The Q9 complex turned out to present a rather boring 9-amino acid peptide6 that, to my eye, could have been cheerfully presented by any of a hundred classical MHC class I complexes.

So basically, this is a very conventional-looking anti-viral response, but directed against an unconventional MHC. There are occasional hints in the literature that this might be more than a one-off,7  though it’s not clear how common it is.  (This unconventional response might normally be drowned out by the conventional response, so that it’s hard to see unless you look in the MHC class I knockout mice.)

Why is this interesting (apart from the obvious point that anything remotely to do with MHC is intrinsically interesting, of course)? As I said, classical MHC is highly polymorphic, while non-classical MHC is not. There are only a handful of Q9 alleles known. If you made an antiviral vaccine with a peptide that binds to Q9, it should work in most mice, whereas if you make a similar vaccine directed to classical MHC class I, you’d need to tailor the vaccine to each individual mouse strain. Humans don’t have Q9 (the non-classical MHC are much less conserved between species than are the highly conserved classicals), but they do seem to have analogous proteins that are non-polymorphic and that may be able to work in antiviral contexts.

There’s a couple of other interesting things about this (Q9 binds to a wide range of peptides,8 for example, which reminds me of an existential question I had that was prompted by chicken MHC; and Lukacher makes the interesting suggestions that polyomavirus and Q9 might be the product of specific co-evolution), but I have a pair of intrepid little boys who camped out in our back yard for the first time last night, and they are proudly hiking the five feet to the house to tell me all about it now.

  1. Swanson, P.A., Pack, C.D., Hadley, A., Wang, C., Stroynowski, I., Jensen, P.E., Lukacher, A.E. (2008). An MHC class Ib-restricted CD8 T cell response confers antiviral immunity. Journal of Experimental Medicine, 205(7), 1647-1657. DOI: 10.1084/jem.20080570[]
  2. At any rate, the virus titre went up something like 50-fold.[]
  3. A clue came from their previous finding the mice lacking β2-microglobulin were highly susceptible to polyomavirus infection. Many, though not all, non-classical MHC class I proteins need β2-m to form a normal structure.[]
  4. The nonclassical major histocompatibility complex molecule Qa-2 protects tumor cells from NK cell- and lymphokine-activated killer cell-mediated cytolysis. Chiang EY, Henson M, Stroynowski I. J Immunol. 2002 Mar 1;168(5):2200-11. []
  5. Chiang, E.Y., and I. Stroynowski. 2005. Protective immunity against disparate tumors is mediated by a nonpolymorphic MHC class I molecule. J. Immunol. 174:5367-5374.
    Correction of defects responsible for impaired Qa-2 class Ib MHC expression on melanoma cells protects mice from tumor growth. Chiang EY, Henson M, Stroynowski I. J Immunol. 2003 May 1;170(9):4515-23. []
  7. For example, Braaten, D.C., J.S. McClellan, I. Messaoudi, S.A. Tibbetts, K.B. McClellan, J. Nikolich-Zugich, and H.W. Virgin. 2006. Effective control of chronic {gamma}-herpesvirus infection by unconventional MHC Class Ia-independent CD8 T cells. PLoS Pathog. 2:e37.[]
  8. Promiscuous antigen presentation by the nonclassical MHC Ib Qa-2 is enabled by a shallow, hydrophobic groove and self-stabilized peptide conformation.  He X, Tabaczewski P, Ho J, Stroynowski I, Garcia KC.  Structure. 2001 Dec;9(12):1213-24.[]