The Nervous System (Fritz Kahn (1888-1968))
The Nervous System (Fritz Kahn (1888-1968))

Is “immunodominance” just what you get when you measure the wrong place?

Usually, when you look at T cell immune responses to a virus, they’re pretty strongly biased. That is, although the T cells are theoretically, and often observably, able to recognize a wide range of target peptides, the immune response is strongly focused on just a handful of these peptides, while the remaining pool of potential targets is either ignored altogether or given a cursory glance by a handful of T cells. This phenomenon is known as “immunodominance“, and it’s seen with  immune responses to all sorts of pathogens. In some cases — such as for HIV — it’s likely that a strongly immunodominant response is harmful, because it makes it easier for the infecting virus to mutate away from immune control. But in the vast majority of cases the immune response, be it never so immunodominant, does a perfectly good job of controlling the virus; which is why we’re able to easily control most of the viruses that we’re exposed to.

Usually when you measure an immunodominant response, you’ll take lymphocytes from the most abundant, easily-accessed place you can find. That would be blood, in humans; in mice you’d probably take a spleen or lymph nodes.  Some viruses like to hang out in these places, and these include some of the more popular research viruses.

But most of the viruses we’re exposed to don’t infect blood or secondary lymphoid organs; they infect the lungs, or the skin, or neurons, or some other tissue. When we measure the blood response, we believe we’re measuring a good approximation of the real response ongoing in the infected tissue, but that’s mostly been an assumption, not a demonstrated fact.

Recently there’s been some work starting to feel out how similar the tissue response is to the blood/lymphoid organ response. For example, I talked here about work establishing the timing of immune responses in the lungs, vs. the blood. In this case, the overall patterns were similar, though the details were somewhat different.

But that was only really looking at a fairly big picture — overall patterns. What about specifics of target recognition? In particular, is the immunodominance we measure in the blood what actually happens on the battlefield?

I’m only aware of a couple of studies that look at this at all, and those were mainly as asides, noticed in passing. Yewdell’s group has shown in a couple of paper that  infecting mice with poxviruses by different routes leads to differences in immunodominance:1

The latter point is underscored by our observation that the ID hierarchy varies with the route of infection, the first observation of its kind to our knowledge. It will be of great interest to determine the underlying mechanism. 2

I’ve been told of unpublished data that show different immunodominant responses between lung and spleen, as well; also with a poxvirus.

But in those few examples, the epitopes were all known ones.  Known epitopes moved up or down a notch or two in the immunodominance hierarchy. A recent paper from Bob Hendricks’ group3 shows that T cells in the tissues can recognize things that are apparently not seen at all in the blood or spleen.

Baines HSV
Electron tomogram of HSV4

Here they used herpes simplex virus (HSV) in C57BL/6 mice, which have long been believed to almost entirely focus their CD8 T cell response on a single peptide. Hendricks’ group has been looking at the immune response to HSV in the brain, where the virus sets up a latent infection  (I’ve talked about some of his findings here and here).  Contrary to more traditional concepts, it’s now becoming clear (from Hendricks’ work, and that of others) that T cells in the brain are important in controlling latent HSV infection.

In this paper, he found that the immune response in the brain is much more diverse, fairly strongly recognizing at least one  peptide other than the known dominant job.  Because the “normal” (that is, non-neuronal) immune response is so focused, this almost certainly means that the active immune response, down at the pointy end where the T cells are actually working, are responding to altogether different peptides.

It’s generally been assumed, as I say, that the easily-accessed blood or secondary lymphoid tissue is a reasonable approximation of what’s going on in the actual sites of action, in the peripheral tissues — in other words, the idea has been that there’s more or less equal flow of cells between the tissues and the blood and lymph. The recent work on timing and kinetics that I mentioned here sort of supported that assumption, but now we have to wonder whether in fact there’s some kind of filter that keeps some sets of T cells from entering, or staying in, the blood.

We also have to wonder if the whole “immunodominance” paradigm is what we think it is. Could immunodominance represent the filter between blood and tissues, rather than the actual formation of responses? I actually don’t think that would explain immunodominance in general (for one thing, we see strong immunodominance for viruses of lymphocytes, where the blood is the site of infection, so there shouldn’t be a filter) but it’s something to factor in.

  1. D. C. Tscharke (2006). Poxvirus CD8+ T-Cell Determinants and Cross-Reactivity in BALB/c Mice Journal of Virology, 80 (13), 6318-6323 DOI: 10.1128/JVI.00427-06
    D. C. Tscharke (2005). Identification of poxvirus CD8+ T cell determinants to enable rational design and characterization of smallpox vaccines Journal of Experimental Medicine, 201 (1), 95-104 DOI: 10.1084/jem.20041912[]
  2. D. C. Tscharke (2005). Identification of poxvirus CD8+ T cell determinants to enable rational design and characterization of smallpox vaccines Journal of Experimental Medicine, 201 (1), 95-104 DOI: 10.1084/jem.20041912[]
  3. B. S. Sheridan, T. L. Cherpes, J. Urban, P. Kalinski, R. L. Hendricks (2008). Reevaluating the CD8 T cell response to HSV-1: Involvement of CD8 T cells reactive to subdominant epitopes Journal of Virology DOI: 10.1128/JVI.01699-08[]
  4. Electron tomogram of a HSV nucelocapsid completing envelopment , from Baines, J. D., C. E. Hsieh, E. Wills, C. Mannella, and M. Marko. 2007. Electron tomography of nascent herpes simplex virus virions. J Virol 81: 2726-2735.[]