Smallpox pustules (R. Carswell, 1831)
Smallpox pustules
(R. Carswell, 1831)

In contrast to the many viruses that block antigen presentation by MHC class I, only a handful appear to block presentation by MHC class II.  I don’t understand why any would try to block MHC class II in the first place, but another example of it has just been published.

A little background: Major histocompatibility complexes (MHC) are recognized by T cells. T cells come in several flavors, the best-understood of which are CD4 (T Helper) and CD8 (cytotoxic T lymphocyte; CTL) lymphocytes. CD8 T cells are fairly specialized to deal with cells infected with viruses;1 they recognize MHC class I. CD4 T cells are at the top of the adaptive immune response; they coordinate subsequent responses, by calling in other cell types, driving antibody or CTL responses, and so on.

MHC class I is on the surface of most cells, as you’d expect, because most cells can be infected with viruses. MHC class I is, among other things, a way of directing the CTL attack to the appropriate, virus-infected, cell, and so they deal, fairly strictly, with what’s going on inside their own particular cell. They don’t take up proteins from outside the cell, because then the cell might get killed when it’s actually a neighbor that’s infected. 2

MHC class II, on the other hand, is a general alarm call that signals “Something’s invading the body, somewhere”. MHC class II is only on a limited number of cells, but those cells do take up protein from outside themselves and show it to CD4 T cells. Presentation on MHC class II does not mean that the particular cell is infected.

So it’s quite logical that viruses would be interested in blocking MHC class I, and as I say there are now many examples of viruses that do so. It’s also logical for viruses to want to block MHC class II, since doing so would reduce all the immune responses against them — antibodies, T cells, whatever.

But how would that work? Again: The cells that do MHC class II antigen presentation are not necessarily infected cells. If a virus is going to block MHC class II, it would have to go out of its way infect the MHC class II-presenting cells (known as professional antigen-presenting cells; APC). Not only that, it would probably have to infect a lot of them, to make a real impact on the overall CD4 T cell response, because even a few unaffected APC will drive a fairly significant immune response, making the suppressed ones irrelevant.

So even though viruses might “want” to block MHC class II, there are practical problems that make it hard to do. Nevertheless, there are a couple of viruses who have genes that can block MHC class II. Human cytomegalovirus is the clearest example, I think,3 and several groups have shown that vaccinia virus blocks MHC class II presentation in infected cells.4 Now a paper in Virology5 argues that the vaccinia gene catchily called “A35” is responsible for this block. Since close relatives of A35 are present in many other poxviruses, MHC class II blockade may be widespread in this family.

A35 colocalizes with RhoB in endosomes
Colocalization between A35 and RhoB in endosomes5

The data are reasonably convincing, though there are some complications. 6 But I’m still puzzled by how this is supposed to work. Vaccinia virus, and poxviruses in general, aren’t renowned for infecting dendritic cells and macrophages, which are the cell types they’d have to efficiently target if MHC class II blockade was to help them.

Removing A35 from vaccinia makes it much less virulent in mice:

A mutant A35 deletion virus (A35?) replicated normally in several tissue culture cell lines, but was highly attenuated (100–1000 fold) in the intranasal and intraperitoneal mouse challenge models7

And apparently this is associated with a reduced immune response to the virus:

Thus far our animal model data are consistent with this hypothesis, showing a reduction in both VV specific antibody and splenic T lymphocyte responses. 8

Which is consistent with a blockade of MHC class II, true, but if you have reduced viral replication for any reason you’d also expect reduced immune responses, because there would be less viral antigen to drive the response. That is, even though A35 blocks MHC class II, and A35 increases virulence, I’m not convinced that A35 increases virulence because it blocks MHC class II. Viral proteins are notoriously multifunctional, and I wonder if the MHC class II blockade is just one function of A35; or perhaps even if it’s just a side-effect of the “real” virulence function.

I’m open to the notion that A35 (and other viral proteins) are true MHC class II blockers, and that this is functionally important, but I’d like to see more data before I put it in the bank.

  1. Also, intracellular bacteria, intracellular parasites, and tumor cells[]
  2. There are exceptions to this rule, including an important phenomenon called “cross-priming” or “cross-presentation”, but that’s not relevant to this discussion now.[]
  3. For example, Johnson DC, Hegde NR. Inhibition of the MHC class II antigen presentation pathway by human cytomegalovirus. Curr Top Microbiol Immunol. 2002;269:101-15.[]
  4. For example, Li, P., Wang, N., Zhou, D., Yee, C.S., Chang, C.H., Brutkiewicz, R.R., Blum, J.S., 2005. Disruption of MHC class II-restricted antigen presentation by Vaccinia virus. J. Immunol. 175 (10), 6481–6488.[]
  5. Rehm, K., Connor, R., Jones, G., Yimbu, K., & Roper, R. (2009). Vaccinia virus A35R inhibits MHC class II antigen presentation Virology DOI: 10.1016/j.virol.2009.11.008[][]
  6. For example, it looks as if there may be other genes, besides A35, that also contribute to MHC class II blockade.[]
  7. Roper, R.L., 2006. Characterization of the Vaccinia virus A35R protein and its role in virulence. J. Virol. 80 (1), 306–313.[]
  8. Rehm, K.E., Jones, G.J.B., Tripp, A.A., Metcalf, M.W., and Roper, R.L., in press. The Poxvirus A35 Protein is an Immunoregulator. J. Virol.[]