As a scientist, I’m comfortable with being wrong most of the time. I’m used to it. But when I make a throwaway comment in a blog and get smacked down in PNAS the following week … well, it seems like overkill, you know?

It’s not quite that bad. A couple weeks ago I was talking about the possibility that tuberculosis-specific T cells were mainly restricted by HLA-B as proposed by Lewinsohn et al.1 I wasn’t very enthusiastic about the idea, suggesting that the skewing they saw was probably just chance. I did admit that there was some biological plausibility to the possibility, but I was mainly thinking about some kind of allele-specific immune evasion. Now, Harari et al argue in the latest PNAS that there is a fundamental difference between CTL restricted by HLA-B, and those restricted by HLA-A.

HLA-A and HLA-B are two distinct major histocompatibility class I genes. There are three classical class I genes in humans (and many other species), with A and B being the most important for T cell recognition. (Here is a map of the human MHC region — HLA-A is way over to the left, in among a bunch of non-classical MHC class I genes, while HLA-B and C are closer to the middle, to the right of the pinkish-shaded Class I region.) Each of HLA-A, B, and C has many different alleles among the human population (HLA-A, B, and C are not alleles of each other, a mistake a lot of people make — they are independent, if linked, genes.) HLA-A and B are typically around 80% identical at the protein sequence level (different alleles within A or B are around 90-95% identical), they look pretty much identical structurally2, and in general they’re hard to tell apart. The only things that I can think of where HLA-A and B differ is that (1) HLA-B has been evolving faster, and (2) HIV is more likely to be controlled by HLA-B than A alleles — something that I, and I think just about everyone, put down to the allelic differences (i.e. different viral peptides being bound) rather than any general HLA-A vs. B distinction. So far as I can remember, no one has ever suggested that they have functional differences as far as T cells go.

Recently it’s been suggested that CTL fall into two broad categories, “polyfunctional” and “only effector”, and that the former category is more important for controlling viruses3. Harari et al4 are now suggesting that these different categories are more associated with HLA-B or -A, respectively:

Polyfunctional CD8 T cell responses, also including IL-2 production and Ag-specific proliferation, are predominantly driven by virus epitopes restricted by HLA-B alleles. … Conversely, HLA-A-restricted epitopes are mostly associated with “only effector” IFN–secreting, with cytotoxicity, and with the lack of IL-2 production and Ag-specific proliferation. … Thus, the functional profile of the CD8 T cell response is strongly influenced by the extent to which there is stimulation of polyfunctional (predominantly restricted by HLA-B) versus only effector (restricted by HLA-A) T cell responses.

It’s an interesting idea. However, their data are not really striking — to me at least. The differences they show in polyfunctional CTL have HLA-A restricting, for example, 0.1% to HLA-B’s 0.25% of the population — not so exciting. The stats they show have P values that are officially statistically significant but aren’t really overwhelming — 0.03, 0.02 — and I question whether the stats are done correctly in all cases (e.g. in one part of Figure 3 where there are overlapping error bars and an N of 5, but they show a P value of 0.005, which just doesn’t look right, unless I’m missing something). They do call the effect “skewing”, which is a conservative claim, so I’ll tentatively accept that far. But I’d really like to see this replicated by a different group, and extended in a larger dataset, before I am completely convinced.

  1. Immunodominant Tuberculosis CD8 Antigens Preferentially Restricted by HLA-B. Lewinsohn, D. A., Winata, E., Swarbrick, G. M., Tanner, K. E., Cook, M. S., Null, M. D., Cansler, M. E., Sette, A., Sidney, J., and Lewinsohn, D. M. (2007). PLoS Pathog 3, e127. []
  2. The ribbon diagrams here are of HLA-A*1101 and HLA-B*2709 []
  3. Reviews: Harari, A., Dutoit, V., Cellerai, C., Bart, P. A., Du Pasquier, R. A., and Pantaleo, G. (2006). Functional signatures of protective antiviral T-cell immunity in human virus infections. Immunol Rev 211, 236-254. and Harari, A., Dutoit, V., Cellerai, C., Bart, P. A., Du Pasquier, R. A., and Pantaleo, G. (2006). Functional signatures of protective antiviral T-cell immunity in human virus infections. Immunol Rev 211, 236-254. []
  4. Harari, A., Cellerai, C., Bellutti Enders, F., Kostler, J., Codarri, L., Tapia, G., Boyman, O., Castro, E., Gaudieri, S., James, I., John, M., Wagner, R., Mallal, S., and Pantaleo, G. (2007). Skewed association of polyfunctional antigen-specific CD8 T cell populations with HLA-B genotype. Proc Natl Acad Sci U S A 104:16233-1623 []