NK cells ganging up on a tumor cell
NK cells ganging up on a tumor cell

A couple of recent papers describe immune evasion of natural killer cells by viruses. One of the interesting things is that both of the viral genes responsible are  multifunctional, apparently blocking both T cell and NK cell recognition simultaneously.

Immune evasion of cytotoxic T lymphocytes (CTL) by blocking the class I major histocompatibility complex (MHC class I) pathway was first described over 20 years ago.  The first viral gene shown to block MHC class I was in adenoviruses, the E3gp19K gene of adenovirus types 2 and 5. That was way back in 1985,1 but though E3gp19K has been studied pretty extensively in the interim it still throws out occasional surprises. For example, the original description of E3gp19K showed that it binds physically to MHC class I molecules, preventing them from reaching the surface, and it wasn’t until 15 years later that Frances Brodsky’s group showed that E3gp19K can also bind to the TAP peptide transporter,2 blocking MHC class I antigen presentation in a completely different way.

So viral evasion of CTL has been described for a long time, but our understanding of natural killer (NK) evasion lagged for a while, mostly because our understanding of NK target recognition lagged that of CTL recognition and MHC class I antigen presentation. (See my previous article here for more detail, including a rather attractive graph of the number of references for each field.)

NK and tumor cellRecently, as tools and understanding improved there’s been quite a bit more attention paid to the subject, and a number of well-defined viral NK evasion mechanisms have been described.3 The two I’m talking about today are the Kaposi’s sarcoma herpesvirus (HSHV) gene K5,4 and none other than our old friend E3gp19K. 5

K5, like E3gp19K, was first identified as a CTL evasion molecule;6 it grabs MHC class I on the cell surface and forces it to be degraded. It’s a remarkably versatile molecule, in that it can also cause degradation of at least seven other cell-surface receptors,7 and one of the very early observations was that K5 also renders cells resistant to NK cells.8 The latest paper4 adds a ninth, tenth, and eleventh notches to K5’s gun: MICA, MICB, and AICL, all of which are NK ligands. (In fact, they’re NK ligands in two separate pathways, so the famous redundancy of NK cell recognition is being attacked here.)

Blood cells including NK cellsK5 acts on these ligands in the same general way it acts on its other targets: It ubiquitinates them and causes them to be internalized and (in some cases) degraded. Similarly, E3gp19K’s new activity is in line with its previously-described talents: It binds to MICA and MICB and prevents them from leaving the ER, so they’re not available for NK cell to bind to. MICA and MICB are in the same general family as MHC class I (see my Guide to the MHC Family) and E3gp19K seems to bind to them in the same way as it does to other MHC class I molecules.

In the big picture, I think it’s not at all surprising that these viruses apparently block NK cell recognition — I’m sure that most, if not all, of the large DNA viruses do so — but it’s nice to have some molecular targets and interactions identified. It’s pretty impressive that these viruses are able to perform such a complex set of actions with single (small!) molecules, and at the molecular level it’s going to be a fascinating story to find out how K5 handles such a diverse range of targets.

One other thing I wonder about — it’s been assumed that E3gp19K is an anti-CTL molecule, but (as I observed here) the actual evidence for this is pretty feeble. What’s more, I’ve been looking at adenovirus effects on MHC class I lately myself, and the most striking thing about it is just how pathetic it is — the effect of E3gp19K on MHC class I expression is pretty unimpressive (as was noted by Routes and Cook many years ago9 ). I wonder if the effect on classical MHC class I is a mere side effect, with the major function of E3gp19K in pathogenesis being NK cell evasion. And given that thought, I wonder if some other viral immune evasion molecules that have been described as CTL resistance factors are in fact mainly NK resistance factors, with CTL being minor or accidental targets.

  1. Burgert, H.-G., and S. Kvist. 1985. An adenovirus type 2 glycoprotein blocks cell surface expression of human histocompatibility class I antigens. Cell 41:987-97. []
  2. Bennett, E. M., Bennink, J. R., Yewdell, J. W., and Brodsky, F. M. (1999). Cutting edge: adenovirus E19 has two mechanisms for affecting class I MHC expression. J Immunol 162, 5049-5052.[]
  3. There’s a review in Immune evasion of natural killer cells by viruses
    Stipan Jonjića,Marina Babića, Bojan Polića and Astrid Krmpotića
    Current Opinion in Immunology 20:30-38 (February 2008) doi:10.1016/j.coi.2007.11.002 []
  4. Thomas, M., Boname, J.M., Field, S., Nejentsev, S., Salio, M., Cerundolo, V., Wills, M., Lehner, P.J. (2008). Down-regulation of NKG2D and NKp80 ligands by Kaposi’s sarcoma-associated herpesvirus K5 protects against NK cell cytotoxicity. Proceedings of the National Academy of Sciences, 105(5), 1656-1661. DOI: 10.1073/pnas.0707883105[][]
  5. McSharry, B.P., Burgert, H., Owen, D.P., Stanton, R.J., Prod’homme, V., Sester, M., Koebernick, K., Groh, V., Spies, T., Cox, S., Little, A., Wang, E.C., Tomasec, P., Wilkinson, G.W. (2008). Adenovirus E3/19K Promotes Evasion of NK Cell Recognition by Intracellular Sequestration of the NKG2D Ligands MICA and MICB. Journal of Virology DOI: 10.1128/JVI.02251-07[]
  6. Ishido, S., Wang, C., Lee, B. S., Cohen, G. B., and Jung, J. U. (2000). Downregulation of major histocompatibility complex class I molecules by Kaposi’s sarcoma-associated herpesvirus K3 and K5 proteins. J Virol 74, 5300-5309.[]
  7. Mansouri M, Douglas J, Rose PP, Gouveia K, Thomas G, Means RE, Moses AV, Fruh K (2006) Blood 108:1932-1940;
    Sanchez DJ, Gumperz JE, Ganem D (2005) J Clin Invest 115:1369-1378;
    Coscoy L, Ganem D (2001) J Clin Invest 107:1599-1606;
    Bartee E, McCormack A, Fruh K (2006) PLoS Pathogens 2:e107;
    Lehner PJ, Hoer S, Dodd R, Duncan LM (2005) Immunol Rev 207:112-125;
    Li Q, Means R, Lang S, Jung JU (2007) J Virol 81:2117-2127[]
  8. Ishido, S., Choi, J. K., Lee, B. S., Wang, C., DeMaria, M., Johnson, R. P., Cohen, G. B., and Jung, J. U. (2000). Inhibition of natural killer cell-mediated cytotoxicity by Kaposi’s sarcoma-associated herpesvirus K5 protein. Immunity 13, 365-374.[]
  9. Routes, J. M., and Cook, J. L. (1990). Resistance of human cells to the adenovirus E3 effect on class I MHC antigen expression. Implications for antiviral immunity. J. Immunol. 144, 2763-2770. []