T cell activation

T cell activation

Immunodominance is one of the many critical, yet poorly understood, phenomena associated with antiviral immunity. Why is it that one particular viral peptide may be recognized by as many as 1% of all the cytotoxic T lymphocytes (CTL) in the body, while a different epitope may be recognized only by 0.001%? There are obvious implications for vaccine design and development; yet we really have little idea of the causes. People have proposed all kinds of explanations — kinetics of peptide presentation, kinetics of T cell response, number of T cell clones, amount of peptide presented — and each of the suggestions has some support but doesn’t seem to explain every instance.

One of the problems is the technical difficulty involved. Accurately quantifying the minute, highly localized amounts of peptide involved, or the tiny handful of cells that could respond, has simply been out of our reach; until very recently.

About a year back, Marc Jenkins’ group described a new technique for measuring very small numbers of T cells in mice1 and came up with some interesting numbers. They looked at three epitopes (for CD4, T helper, T cells, not CTL; but guesses have been that the two groups of T cells have similar numbers of precursors) and concluded that the epitopes had 190, 20, and 16 precursor T cells specific for them. What’s more, the more T cell precursors there are, the higher the ultimate T cell response to the epitope — the more immunodominant that epitope is.

I commented on the paper at the time and said “It’s an interesting suggestion, and their data certainly are suggestive. I’m sure there will be more epitopes examined by this technique over the next little while, so we’ll see how well it holds up.” Now, a year later, we’re seeing the first followup, and it turns out to hold up pretty well; although there are, not surprisingly, some added complexities.

The followup is from Leo Lefrancois’s group in UConn.2 I will skip over their controls, except to say that they did a bunch of ingenious controls to demonstrate that they really were looking at what they claim to be.

First, they looked at a half-dozen known epitopes and asked how many precursor CTL there were for each. Their numbers were in the same ballpark as the CD4 precursors measured earlier; they came up with a range from 80 to 1200 CTL (average, 120-160) specific for their various epitopes. This is somewhat larger than the Moon et al. estimates I mentioned earlier, but I think that these epitopes were all, or almost all, fairly abundant to start with, so it’s pretty consistent.

T cell - dendritic cell interactions

T cell and dendritic cell interactions

They also used the technique for an extremely cool experiment. They infected mice with viruses, and then tracked through the number of CTL present each day. This way they were able to ask the exciting question, When is the immunodominance hierarchy set?

Moon et al. last year suggested that immunodominance hierarchies are set on day 0; that the number of T cell precursors present determines the size of the response to an epitope. I was a little dubious about that, saying “I think it’s equally likely that while the size of the naive precursor pool is one factor, you can also get different T cell responses out of the same number of precursors, for any of a variety of reasons.”

Here’s ObarĀ  et al.’s conclusion:

Although the M45:Db- and VSV-N:Kb-specific responses differed kinetically, they were of similar overall magnitude, even though their initial precursor frequencies differed on average by 4-fold… These data suggested that interclonal competition for resources (i.e., APC interactions, growth factors, or costimulatory molecules) prior to the peak of the response was important in modulating overall clonal expansion.

(My emphasis)

So the bad news, I guess, is that there may not be a single simple explanation for immunodominance, at least for CTL. However, precursor frequency does seem to be one factor — and an important one — in setting CTL immunodominance hierarchies, and knowing the timing of other factors (hierarchies are set around day 3, Obar et al. determined) should be a big help in narrowing down possibilities.

  1. Naive CD4(+) T Cell Frequency Varies for Different Epitopes and Predicts Repertoire Diversity and Response Magnitude. Moon JJ, Chu HH, Pepper M, McSorley SJ, Jameson SC, Kedl RM, Jenkins MK. Immunity. 2007 Aug;27(2):203-13.
    Commentary on the paper, by Mark Davis, here: The T Cell Repertoire Comes into Focus. Davis MM. Immunity. 2007 Aug;27(2):179-80. []
  2. Obar, J., Khanna, K., LeFrancois, L. (2008). Endogenous Naive CD8+ T Cell Precursor Frequency Regulates Primary and Memory Responses to Infection. Immunity, 28(6), 859-869. DOI: 10.1016/j.immuni.2008.04.010[]