Mystery Rays from Outer Space

Meddling with things mankind is not meant to understand. Also, pictures of my kids

December 8th, 2010

Do TRegs discriminate?

As I’ve noted several times before, regulatory T cells are important reasons for the poor immune response to tumors. TRegs are normal components of an immune response, “designed” to keep inflammation from running riot in general and to prevent responses to self-antigens in particular. Whether it’s because tumors are mostly (though not solely) self antigens, because tumors are chronic sources of stimulation that could lead to inflammation running riot, or because tumors “learn” how to specifically trigger TReg-like responses, TRegs are common features of tumors.

Eliminating TRegs, in mouse models of cancer, often allows a strong immune response to the tumor. An interesting spin on this was shown in a recent J Immunol paper.1 It seems that the TRegs don’t generally suppress all the response, they shut down the responses to some targets harder than others:

Our results indicate, therefore, that depletion of Tregs uncovers cryptic responses to Ags that are shared among different tumor cell lines. CT26-specific T cell responses can be elicited by different forms of vaccination in the presence of regulatory cells, but in these cases T cell responses are highly focused on a single tumor-specific epitope …Taken together, these data suggest that immune responses to some Ags are more tightly regulated than others.  1

In other words, even though you might be able to force a protective immune response to a tumor by vaccinating in the presence of TRegs, when you get rid of TRegs the response is broader, and targets T cell epitopes that otherwise wouldn’t look like they’re epitopes at all.

I wonder if this goes on with “normal” (say, viral or other non-tumor) epitopes – whether this sort of thing might help explain some forms of immunodominance. I kind of doubt it, but the phenomenon does sounds a little like revealing a subdominant response.

I wonder also how this ties in with a recent paper that suggested TRegs in tumors are highly focused on a small subset of tumor epitopes. Could they be more broadly-based, but on epitopes that are otherwise invisible? Again, I kind of doubt it, but it’s an intriguing idea.  Maybe the universe of tumor epitopes available for attack is much larger than we realize.


  1. James, E., Yeh, A., King, C., Korangy, F., Bailey, I., Boulanger, D., Van den Eynde, B., Murray, N., & Elliott, T. (2010). Differential Suppression of Tumor-Specific CD8+ T Cells by Regulatory T Cells The Journal of Immunology, 185 (9), 5048-5055 DOI: 10.4049/jimmunol.1000134[][]
November 3rd, 2010

Shield or target? A downside of immune evasion

T cells & herpes simplex
T cells (green) and herpesvirus-infected cells (red)
(from Akiko Iwasaki)

We know that lots of viruses, especially herpesviruses, block antigen presentation. The assumption has been that they are thereby preventing T cells from recognizing infected cells, though long-term readers of this blog1 will know that I’ve been puzzled about the details of this for quite a while.

A recent paper2 raises yet another complication for this pathway: In humans3 there are T cells that specifically recognize cells in which antigen presentation is blocked:

Our data indicate that the human CD8+ T cell pool comprises a diverse reactivity to target cells with impairments in the intracellular processing pathway2

If so, you might wonder why the viruses would bother blocking antigen presentation. They might avoid recognition by T cells specific for the viral proteins, but at the cost of being recognized and eliminated by the T cells that recognize antigen-presentation-defective cells.

As always, I don’t have an answer. I do have the unhelpful observation that viruses are incredibly subtle and efficient, and given that herpesviruses have apparently maintained the ability to block antigen presentation for some 400 million years it’s presumably useful to them. I’ll also add the even more unhelpful observation that immune systems are also incredibly subtle and efficient and have also persisted for 450 million years.

How Not to be Seen

However, there may be a clue in the techniques that Lampen et al used to turn up this subset of T cells: They used multiple rounds of stimulation, which is going to expand these cells massively. We don’t know how abundant they are inside a normal human – perhaps they are so rare that they don’t have a chance to impinge on herpesvirus infection early enough.

The catch with that, though, is that tumors also frequently get rid of antigen presentation via mutation; in fact, eliminating antigen presentation seems to be one of the most common forms of mutations in cancers, suggesting that it’s an important part of their ability to survive and expand in the face of immune attack. Tumors are immunologically present much longer than viruses ((Although herpesviruses set up a lifelong infection, most of that is generally in a non-immunogenic, latent form). So why doesn’t this long-term tumor presence lead to amplification of these antigen-presentation-deficient-specific T cells that would eliminate the tumor?

My guess here is that this is where TRegs come in. As I said in a recent post, TRegs are very commonly, if not universally, associated with tumors, and prevent immune attack on the tumor. I wonder if the tumors mutate to avoid T cell recognition early in their development, before they are able to trigger the TReg response; that allows them to grow large enough and long enough that by the time the presentation-defect-destroyers kick in, the tumors have their TReg defenders set up.  (I admit that this doesn’t account for the correlation between a tumor’s loss of antigen presentation, and poor prognosis, but I leave this as an exercise for the reader.)

And, of course, where either of these defense systems for the proto-tumor fails, we normally would simply not see any tumor at all. Perhaps this is happening all the time inside us — proto-tumors are being eliminated by T cells, some are mutating their antigen presentation pathway and lasting a little longer and are then eliminated by a different subset of T cells, and we never know it.


  1. If any[]
  2. Lampen, M., Verweij, M., Querido, B., van der Burg, S., Wiertz, E., & van Hall, T. (2010). CD8+ T Cell Responses against TAP-Inhibited Cells Are Readily Detected in the Human Population The Journal of Immunology DOI: 10.4049/jimmunol.1001774[][]
  3. As has been previously shown in mice[]
October 28th, 2010

Immunological standoff

TRegs infiltrate a tumor
TRegs infiltrate into a tumor

There’s increasing evidence supporting the notion that tumors are often not rejected by the immune system because regulatory T cells actively block the immune response to the tumor cells. 1

That means that within the tumor, two branches of the immune response are fighting it out. If the TRegs win, the tumor will not be rejected (and may eventually kill the host); if the rejection branch2 wins, the tumor may be rejected and the host may survive a little longer.

Both TRegs and rejection-branch T cells are driven by specific antigen. That is, as opposed to the general patterns that drive innate immune responses, the T cells are activated by peptides associated with major histocompatibility complexes (mainly class II MHC, for the TRegs).

So that raises an interesting question: What specific peptides activate the TRegs in the tumors, and are they different from the ones that activate rejection-type CD4s?

The question is even more interesting than it may seem at first glance, because3 there are different TReg subsets with different peptide preferences. One set of TRegs likes to see ordinary self-peptides: Peptides that are naturally present, and that should not be rejected because, well, they’re part of you. “Normal” rejection-type T cells don’t see those peptides, because those that do are killed during their development (or are converted into TRegs during development, probably). The other group of TRegs sees foreign peptides, that would be expected to be rejected. You need these TRegs as well, because there are times when a chronic immune response, even to a foreign invader, is more harmful than the invader itself; so under those circumstances, some rejection-type T cells get converted into TRegs, and those can shut down the response to the invader, hopefully to reach a happy accommodation.

Are the TRegs in tumors the first kind, that are activated by the normal self-antigens that are present in the tumor cells (which are, remember, originally you to start with)? Or are they the second type, responding to the foreign antigen present in the tumor (mutated proteins, say, or over-expressed growth factors) but converted into a TReg type from a rejection-type when the tumor foreign antigens proved to be a chronic stuimulus?

Reservoir Dogs StandoffA recent paper4 suggests it’s the latter:

This allows us to ask whether tumor-associated Treg cells arise from the repertoire of TCRs used by natural Treg cells or from the repertoire used by effector cells. We show that Treg population in tumors is dominated by T cells expressing the same TCRs as effector T cells. These data suggest that Treg in tumors are generated by expansion of a minor subset of Treg cells that shares TCRs with effector T cells or by conversion of effector CD4+ T cells and thus could represent adaptive Treg cells. 4

If this is generally true (and the authors do offer a helpful series of caveats) it has a very important implication. There’s a huge amount of interest in tumor vaccines — identify an antigen specific for the tumor, and induce a potent immune response to it, in the hope that T cells will then reject the tumor. But you see the problem: If the TRegs are stimulated by the same antigen, then your vaccine is going to increase both sides — the rejection branch and the TReg branch — and you’re no further ahead than when you started! This may be one of the reasons that tumor vaccines have been only intermittently effective. But it does make even more attractive another approach toward cancer immunization, where TRegs are specifically blocked, hopefully allowing the already-present rejection-type5 T cells to kick in and, maybe, eliminate the tumor:

This further suggests that improved cancer immunotherapy may depend on the ability to block tumor-antigen induced expansion of a minor Treg subset or generation of adaptive Treg cells, rather than solely on increasing the immunogenicity of vaccines. 4


  1. I’m not quite comfortable with the phrasing here, but I can’t come up with a non-lawyerly, succinct way to phrase it. TRegs are part of the immune system, and so when they’re active the immune system isn’t blocked, it’s highly functional. What’s being blocked is what we traditionally think of as an immune response — the aggressive response that causes inflammation and that kills targets — while the TReg form is the branch of the immune response that prevents all those things. When TRegs are dominant, the immune response isn’t easily visible, but it’s still an active immune response.[]
  2. Again, not happy with the term; if anyone has a more felicitious phrase, let me know[]
  3. My qualifier here is “For now”, because this is a rapidly-changing field that has kind of outstripped my ability to follow it right now; I’m not quite sure whether this is the consensus view any more[]
  4. Kuczma, M., Kopij, M., Pawlikowska, I., Wang, C., Rempala, G., & Kraj, P. (2010). Intratumoral Convergence of the TCR Repertoires of Effector and Foxp3+ CD4+ T cells PLoS ONE, 5 (10) DOI: 10.1371/journal.pone.0013623[][][]
  5. Having typed that a dozen times here, I like it less than ever[]
October 7th, 2010

MHC vs pathogens: Evolution showdown

ShowdownI’m not finding time to give these papers a full post each, so let me pool together several in the same theme: MHC alleles and protection against pathogens.

It’s generally accepted that the reason there are so many MHC alleles is related to their ability to protect against pathogens.1 The version is probably the frequency-dependent selection model. According to this, pathogens are selected to be resistant to common MHC alleles, so individuals with rare alleles have a selective advantage and those alleles become more common, until pathogens are selected for resistance to them in turn. (Described in more detail here.).

The particular steps in this concept are each fairly straightforward and reasonably well supported. We know that different MHC alleles can be more or less effective against pathogens; we see some instances of pathogens developing resistance to particular MHC alleles, and so on. But it’s been quite difficult to put all the pieces together. The best examples of pathogens evolving resistance to MHC alleles, for instance, are within a single host, in the case of HIV. When we look at even this virus over a population instead, it’s much harder to detect any particular adaptation to MHC (though there may be some).

The problem is (probably) that we’re looking at a single frame of a movie. This is a dynamic process, as the pathogens and the individuals within a population co-evolve. It’s hard to see fossil MHC alleles and just as hard to see fossil viral epitopes. The snapshot we see today may be at any point along the process – the pathogen may have the upper hand, the hosts may, or they may be perfectly balanced. (Also, of course, the host need to deal with thousands of pathogens, while each pathogen may focus on one or a handful of hosts. It would take a fairly assertive pathogen to single-handedly push a host population toward differential allele usage. The host’s version of the movie frame would actually be a blur of a thousand frames from a thousand movies, each of which is shown at different speeds and with a different starting point, all overlapping and interacting with each other.)

So observations supporting the frequency-dependent model have been rather scarce; in fact, instances where MHC alleles differentially affect pathogens are themselves relatively scarce, and those are the starting points from which frequency-dependent selection arises. So I’m always intrigued when we learn of cases where there are specific resistance and susceptibility alleles of MHC for particular pathogens, in the wild, and in a population rather than an individual.

Here are some I’ve noticed in the past few weeks.

Koehler, R., Walsh, A., Saathoff, E., Tovanabutra, S., Arroyo, M., Currier, J., Maboko, L., Hoelsher, M., Robb, M., Michael, N., McCutchan, F., Kim, J., & Kijak, G. (2010). Class I HLA-A*7401 Is Associated with Protection from HIV-1 Acquisition and Disease Progression in Mbeya, Tanzania The Journal of Infectious Diseases DOI: 10.1086/656913

Other MHC class I alleles have been shown to be protective against HIV, so this is mainly adding to the list; but it;s a shortish list, so any additions are interesting.

MacNamara, A., Rowan, A., Hilburn, S., Kadolsky, U., Fujiwara, H., Suemori, K., Yasukawa, M., Taylor, G., Bangham, C., & Asquith, B. (2010). HLA Class I Binding of HBZ Determines Outcome in HTLV-1 Infection PLoS Pathogens, 6 (9) DOI: 10.1371/journal.ppat.1001117

An attempt to link observed protective MHC alleles, with the mechanism of protection, concluding that being able to induce T cell recognition of a specific HTLV-1 protein is associated with protection.  This is conceptually similar to the proposed mechanism by which [some] MHC alleles protect against HIV,2 where a specific peptide target can’t mutate away from T cell recognition.

Appanna, R., Ponnampalavanar, S., Lum Chai See, L., & Sekaran, S. (2010). Susceptible and Protective HLA Class 1 Alleles against Dengue Fever and Dengue Hemorrhagic Fever Patients in a Malaysian Population PLoS ONE, 5 (9) DOI: 10.1371/journal.pone.0013029

They identify MHC alleles that may be associated with protection against disease, and protection against severe disease.  I’m a little uncomfortable with the relatively small number of patients involved here (less than 100), and would like to see it confirmed in a larger study.

Guivier, E., Galan, M., Male, P., Kallio, E., Voutilainen, L., Henttonen, H., Olsson, G., Lundkvist, A., Tersago, K., Augot, D., Cosson, J., & Charbonnel, N. (2010). Associations between MHC genes and Puumala virus infection in Myodes glareolus are detected in wild populations, but not from experimental infection data Journal of General Virology, 91 (10), 2507-2512 DOI: 10.1099/vir.0.021600-0

We revealed significant genetic differentiation between PUUV-seronegative and -seropositive bank voles sampled in wild populations … Also, we found no significant associations between infection success and MHC alleles among laboratory-colonized bank voles, which is explained by a loss of genetic variability that occurred during the captivity of these voles.

The difference between wild and captive voles is reminiscent of the difficulty and confusion involved in MHC function in lab mice. In at least one set of experiments, it was necessary to have semi-feral mice before mechanisms could be teased apart.


  1. There are a few alternate explanations, but even things like the mate-selection hypothesis, which I discussed here and here, usually still involve an element of protection against pathogens.[]
  2. HIV and HTLV are related viruses, for what that’s worth[]
September 20th, 2010

MHC on the brain

Needleman et al 2010 Fig 1
Needleman et al, 1 Fig 1: Section of rat vidual cortext stained for MHC class I (green) and nuclei (red)
Needleman et al Fig 1
Needleman et al, 1 Fig 1: Section of rat vidual cortext stained for MHC class I (green) and nuclei (red)

I said the other day that not all MHC class I molecules are involved in immunity, and used HFE as an illustration of one that’s not directly involved in immunity. It’s worth mentioning, though, that even those MHC class I molecules that are involved in immunity, aren’t necessarily always involved in immunity.

That may need a little clarification. “MHC class I” molecules include a wide range of members. The ones most people think about2 are the classical members of the family, reasonably enough called “classical MHC class I“, or perhaps MHC class Ia molecules. These are very clearly immune molecules. They’re receptors for cytotoxic T cells and for natural killer cells, they select cells in the thymus, they do everything you’d expect an immune molecule to do.

There are many other family members, though, that are “non-classical” MHC class I, or MHC class Ib molecules. They’re clearly members of the same family, based on their structure: Many of them look, at first and even second glance, almost exactly like a class Ia molecule (see here for some structures). Some of these have clear immune functions (some CD1 molecules seem to be involved in the immune control of certain bacteria, for example).

But others don’t have any apparent immune function. As I say, HFE is one such molecule. It’s a class Ib molecule that looks very much like a class Ia, but it seem to be strictly involved in regulation of iron metabolism. There are quite a few others, as well.

This isn’t surprising. The ancestors of the first MHC class I molecules were probably some kind of cell-interaction molecules, evolved to interface with other cell-surface molecules. The MHC module retains that capability, and it’s a useful tool to include in your generic molecule-binding toolkit. It’s not surprising that variants of MHC class I bind iron, or pheromone receptors, or antibodies, or what have you; because that capability was part of their initial and underlying function.

Which brings me back to my original comment. Not only do variants of MHC class I have various interface capabilities, so do the classical class I molecules themselves. And there’s at least one context where it seems that classical MHC class I molecules act purely in this ancient cell/cell interaction process, without any hint of an immune function: Classical MHC class I molecules are involved in brain development and, perhaps, function. 3

I’m not going to go into a lot of details on the mechanism or the role. For one thing, I don’t know much about brain development; for another, it’s still pretty mysterious as to what exactly MHC class I molecules are doing. But there they are, in the brain during development, and if you get rid of MHC there are at least some subtle defects in brain development.

What I mainly get out of these papers is that brain researchers get much prettier pictures than do immunologists. Admire the ones here1 while we wait for them to figure out what’s going on.


  1. Needleman, L., Liu, X., El-Sabeawy, F., Jones, E., & McAllister, A. (2010). MHC class I molecules are present both pre- and postsynaptically in the visual cortex during postnatal development and in adulthood Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1006087107[][][]
  2. Well, to the extent that most people think about MHC at all, which I realize isn’t all that much[]
  3. Goddard, C., Butts, D., & Shatz, C. (2007). Regulation of CNS synapses by neuronal MHC class I Proceedings of the National Academy of Sciences, 104 (16), 6828-6833 DOI: 10.1073/pnas.0702023104

    Zohar O, Reiter Y, Bennink JR, Lev A, Cavallaro S, Paratore S, Pick CG, Brooker G, & Yewdell JW (2008). Cutting edge: MHC class I-Ly49 interaction regulates neuronal function. Journal of immunology (Baltimore, Md. : 1950), 180 (10), 6447-51 PMID: 18453559

    Goddard CA, Butts DA, & Shatz CJ (2007). Regulation of CNS synapses by neuronal MHC class I. Proceedings of the National Academy of Sciences of the United States of America, 104 (16), 6828-33 PMID: 17420446

    Huh, G. (2000). Functional Requirement for Class I MHC in CNS Development and Plasticity Science, 290 (5499), 2155-2159 DOI: 10.1126/science.290.5499.2155[]

September 7th, 2010

Assassination or accident?

I have as much respect for viruses’ ability to manipulate their host as the next guy, and I’m probably more of a fan of viral immune evasion than that next guy. But I still do think that coincidences do happen.

A paper from John Trowsdale and colleagues1 shows that Kaposi’s Sarcoma Herpesvirus (KSHV) destroys HFE, and they suggest that this is “a molecular mechanism targeted by KSHV to achieve a positive iron balance.” Without dissing their observations (which are perfectly convincing) I’m not entirely convinced by their conclusion. Still, it’s an interesting suggestion, and I’m keen to see some kind of followup to it.

The reason I’m not convinced is that this has the look of a spillover effect to me. We already know that KSHV attacks MHC class I molecules via its K3 and K5 molecules, and that it does so by targeting the cell-surface pool to lysosomes. This is a very familiar pattern; most, if not all, herpesviruses block MHC class I molecules. Although it’s been hard to formally prove “why” herpesviruses do this,2 the general assumption is that this allows the virus to at least partially avoid recognition by T cells, and this lets the virus survive better — perhaps because it builds a larger population very early, or perhaps because it is able to last longer late, or whatever.

At any rate, there’s a fairly simple and logical reason why it would make sense for KSHV to block MHC class I molecules, and as I say they do, in fact, do this. Now, why would they attack HFE? HFE is an iron-binding protein that’s involved in the regulation of iron metabolism. Why would KSHV be interested in iron metabolism?

Quite a few pathogens are actually very concerned about iron metabolism, of course. Bacteria generally need iron for their metabolism,3 and pathogenic bacteria have evolved ways of grabbing iron away from their hosts (while their hosts have evolved way of holding on tighter and tighter to that iron). But in general viruses, as opposed to bacteria, don’t have specific needs for iron. Trowsdale’s group makes the argument — and offers some experimental evidence — that KSHV does in fact want iron. “KSHV presumably down-regulates HFE to affect iron homeostasis,” they say, and “These results indicated an iron requirement for lytic KSHV and with the virus targeting HFE to satisfy this demand.” However, I don’t think they really show this directly; they show that there are changes in iron receptors in the presence of KSHV, but as far as I can see they don’t show that the presence or absence of iron actually affects the virus in any way.

HFE complex HLA-A2 complex
HFE heavy chain (red) complexed with beta-2 microblogulin (blue) HLA-A2 (classical MHC class I) heavy chain (red) complexed with beta-2 microblogulin (blue) and a peptide (green)

So let’s say KSHV doesn’t really care about iron per se. Why is the virus attacking this iron receptor, then? To me, the simpler solution is that it’s just a side effect of the virus attack on MHC class I, because HFE is in fact an MHC class I molecule.4 Not all MHC class I molecules are involved in immunity, and HFE is the classic counterexample, an MHC class I molecule that has a clear non-immune role. 5

Even though HFE has a different role, it has a very similar structure to the classical MHC class I molecules — see the images to the right (click for larger versions), and for more comparisons see my post from a couple of years ago, “MHC Molecules: The Sitcom“.  It doesn’t have the peptide bound in the top groove (green in the HLA-A2 complex here) that classical MHC class I molecules use to provide specific signals to T cells, but it’s very similar. It’s plausible — at least to me — that the virus doesn’t care in the least about iron metabolism, but is just attacking everything on the cell surface that looks like an MHC class I molecule, and HFE is getting caught in the covering fire.

Interestingly, though, this isn’t the first time this has been proposed.  A few years ago a paper from Drakesmith et al proposed pretty much the same model for HIV, via the HIV immune evasion molecule nef.  Nef downregulates a large number of immune-related molecules, and also downregulates HFE. Drakesmith et al, like Trowsdale’s group, argue that this is “deliberate”, and that the modified iron metabolism directly benefits HIV;6 but I don’t know if that’s been followed up (Trowsdale’s paper, surprisingly, doesn’t cite Drakesmith et al).

I’m open to the idea that viruses do “want” to tweak iron metabolism, because that would be pretty cool, but so far I’m leaning to notion that HFE is just an accidental victim of the viral war on immunity.


  1. Rhodes DA, Boyle LH, Boname JM, Lehner PJ, & Trowsdale J (2010). Ubiquitination of lysine-331 by Kaposi’s sarcoma-associated herpesvirus protein K5 targets HFE for lysosomal degradation. Proceedings of the National Academy of Sciences of the United States of America PMID: 20805500[]
  2. I put “why” in quotes because obviously it’s not planned. But it’s easier than saying, “why herpesviruses have evolved this ability” or “what selective advantage this ability confers to the herpesviruses”.[]
  3. I say “generally” because I’m not a bacteriologist, and no doubt there’s some bizarre oddball bug that doesn’t need iron to get along. But I don’t know any of them. As far as I know bacteria all need iron[]
  4. It’s a class Ib molecule, a non-classical MHC class I molecule, but it is MHC class I.[]
  5. It’s worth noting that HFE might — just might — have an immune role, too. There are T cells that recognize HFE. It’s not clear, at least to me, what these T cells do, and whether they have a real function or if it’s just a case –another case? — of accidental spillover.
    Rohrlich PS, Fazilleau N, Ginhoux F, Firat H, Michel F, Cochet M, Laham N, Roth MP, Pascolo S, Nato F, Coppin H, Charneau P, Danos O, Acuto O, Ehrlich R, Kanellopoulos J, & Lemonnier FA (2005). Direct recognition by alphabeta cytolytic T cells of Hfe, a MHC class Ib molecule without antigen-presenting function. Proceedings of the National Academy of Sciences of the United States of America, 102 (36), 12855-60 PMID: 16123136[]
  6. Drakesmith H, Chen N, Ledermann H, Screaton G, Townsend A, & Xu XN (2005). HIV-1 Nef down-regulates the hemochromatosis protein HFE, manipulating cellular iron homeostasis. Proceedings of the National Academy of Sciences of the United States of America, 102 (31), 11017-22 PMID: 16043695[]
September 2nd, 2010

Immunity under natural selection

HapMap 3, officially announced in today’s issue of Nature,1 is an “integrated data set of common and rare alleles” in human populations, built from “1.6 million common single nucleotide polymorphisms (SNPs) in 1,184 reference individuals from 11 global populations“. 

As well as being a resource for genome-wide studies, there are a number of things that can be done with the data directly. One of those is to help identify regions that are under positive natural selection. The authors found a number of them, including several immune-related genes in the Kenyan population.

A little sadly for me, none of these genes are ones I’m particularly familiar with. The three that are listed are:

  • CD226.  This is an activating NK cell receptor. An allelic variant in CD226 has been linked to a number of autoimmune diseases,2 so it wouldn’t be surprising to learn that it’s under some form of selection.  I didn’t check the actual SNP that was shown to be selected, to see if it’s the same one that’s linked to autoimmunity.

  • ITGAE.  This is an integrin3 that’s apparently involved in lymphocyte trafficking.  Allelic variants in ITGAE have been linked to a number of diseases including sarcoidosis4 and ischemic stroke.5

  • DPP7 is dipeptidyl-peptidase 7.  Although I’ve had a strong interest in peptidases for a while6 because of their influence on MHC class I antigen presentation, DPP7 seems to have an unrelated role, that of preventing apoptosis of resting lymphocytes. I don’t know of any links between DPP7 and disease, but obviously altering lymphocyte survival could impact lots of things. 

I’m sure that any more immune-related genes are under strong selection — we know that MHC genes are very strongly and rapidly selected, for example — but they don’t necessarily send up flags in this sort of analysis. 


  1. The International HapMap 3 Consortium (2010). Integrating common and rare genetic variation in diverse human populations Nature, 47, 52-58 DOI: 10.1038/nature09298[]
  2. Douroudis K, Kingo K, Silm H, Reimann E, Traks T, Vasar E, & Kõks S (2010). The CD226 Gly307Ser gene polymorphism is associated with severity of psoriasis. Journal of dermatological science, 58 (2), 160-1 PMID: 20399620

    Maiti AK, Kim-Howard X, Viswanathan P, Guillén L, Qian X, Rojas-Villarraga A, Sun C, Cañas C, Tobón GJ, Matsuda K, Shen N, Cherñavsky AC, Anaya JM, & Nath SK (2010). Non-synonymous variant (Gly307Ser) in CD226 is associated with susceptibility to multiple autoimmune diseases. Rheumatology (Oxford, England), 49 (7), 1239-44 PMID: 20338887[]

  3. Intergrins are cell-surface molecules often involved in cell-cell interactions[]
  4. Heron M, Grutters JC, Van Moorsel CH, Ruven HJ, Kazemier KM, Claessen AM, & Van den Bosch JM (2009). Effect of variation in ITGAE on risk of sarcoidosis, CD103 expression, and chest radiography. Clinical immunology (Orlando, Fla.), 133 (1), 117-25 PMID: 19604725[]
  5. Luke MM, O’Meara ES, Rowland CM, Shiffman D, Bare LA, Arellano AR, Longstreth WT Jr, Lumley T, Rice K, Tracy RP, Devlin JJ, & Psaty BM (2009). Gene variants associated with ischemic stroke: the cardiovascular health study. Stroke; a journal of cerebral circulation, 40 (2), 363-8 PMID: 19023099[]
  6. Pubmed link to my peptidase papers[]
August 3rd, 2010

Lamprey immunity, again

The Lamprey (Yarrell 1835)
From A History of British Fish (William Yarrell, 1835)

I’ve talked about lamprey immune systems several times (here, here, and here). I find them fascinating because it shows both how our own immune system developed, and also shows alternate routes that can lead to a pretty good, but very different, immune system.

Quick background: In order of evolutionary appearance you have sea urchins, lampreys, sharks, reptiles, mammals. (Note that this is not true, it’s no more than a sloppy shorthand for common ancestry, but it’s a handy shorthand for this purpose.  See a phylogenetic tree here.) Mammals have a form of adaptive immune system that includes T lymphocytes and antibodies, and at first glance this whole complex system arose, almost fully-formed, in sharks.1

This has always amazed me, because an adaptive immune system doesn’t work in isolation; the pieces don’t work alone. You need all kinds of moving parts — all the complex molecular pieces that chop and snip DNA to form T cell receptors and antibodies, all the multiple parts of a thymus that screen T cells for functional and safe receptors, the MHC molecules that the receptors see and all the pieces that snip and shuffle around peptides for that system, the spleen and lymph nodes that let lymphocytes interact with other cells, — and it seemed that all these pieces abruptly appeared and put themselves together, like a fine watch, in one evolutionary blink.

When I first learned about this, some 15 or 20 years ago, I told myself that this was an illusion, that once more species were looked at we’d see the history of these moving parts in other common ancestors. Of course, this is exactly what’s happened since then. We see accidental, random parts in sea urchin genomes (I talk about that here) and we see other bits and pieces arising in lampreys and hagfish (in the links at the top).

So in reality, the adaptive immune system didn’t arise all that suddenly after all; the pieces gradually were added over a hundred million years or more, sometimes purely by chance, sometimes for other purposes altogether, and sometimes as components of a prototypic immune system that acted as a foundation for the whole shark thing.2

So that’s the first part of the background: In lampreys, which diverged from the mammalian lineage maybe 450 million years ago, we see many of the pieces of a mammalian adaptive immune system. There are cells that look a lot like lymphocytes, there is something that looks like a spleen. But, as I say, there are none of the familiar pieces that we think of as an adaptive immune system. Lampreys flatly do not have our adaptive immune system:

Nevertheless, the cardinal elements of adaptive immunity, namely Ig, TCR, RAG1 and 2, and MHC class I and II, were conspicuously absent.3

Lamprey "antibody"
Lamprey variable receptor with bound antigen4

But step back a little, and look a little deeper, and we see some familiar parts. Lampreys do, in fact, have variable receptors, just like T cell receptors and antibodies, and those receptors are made by chopping and shuffling genome DNA, just like TcR and antibodies, and are expressed in their lymphocyte-like cells, and some are secreted (like antibodies and B cells) and some are cell-associated (like T cell receptors).

And here’s the other amazing thing: At the molecular level, the lamprey receptors are completely unlike T and B cell receptors. The lamprey lineage came up with a completely different system that allows them to do pretty much the same thing as the shark lineage. Their receptors are different kinds of molecules, and the system that shuffles the genomic DNA is different. 5 Yet, the functional end product is the same — a system that has immunological memory. An adaptive immune response, that’s quite alien to our own, but that works pretty damn well.

Although the Ig-based and VLR-based adaptive immune systems in jawed and jawless vertebrates use different genes and assembly mechanisms, both systems generate diverse repertoires of anticipatory receptors capable of recognizing almost any Ag through the combinatorial assembly of large arrays of partial gene segments. The development of clonally diverse lymphocytes allows for Ag-specific responses and memory, which are lacking in innate immunity.3

There is still a lot we don’t know about lamprey immunity (how does it present self-reative receptors, with no thymus?) but what we do know is just so amazing, I’m completely fascinated by it. It beautifully illustrates two of the basic features of evolution — building on previous structures, whether related or not; and alternate solutions to the same problem. Herrrin and Cooper have a short and dense, but very interesting, review, 3 that prompted this particular post.


  1. That is, in the common ancestor of sharks and mammals, to use a slightly less-sloppy terminology.[]
  2. And of course, the system has continued to evolve. The mammalian system is remarkably similar to the shark in broad strokes, but it’s also very different in many ways.[]
  3. Herrin, B., & Cooper, M. (2010). Alternative Adaptive Immunity in Jawless Vertebrates The Journal of Immunology, 185 (3), 1367-1374 DOI: 10.4049/jimmunol.0903128[][][]
  4. B. W. Han, B. R. Herrin, M. D. Cooper, I. A. Wilson (2008). Antigen Recognition by Variable Lymphocyte ReceptorsScience, 321 (5897), 1834-1837 DOI: 10.1126/science.1162484[]
  5. Though there are some common pieces that hint at a common ancestor of the two systems, maybe.[]
June 22nd, 2010

Dual-specificity T cells and autoimmunity

Painting of TcR interacting with artrificial membranes by Raghuveer Parthasarathy
TcR interacting with artificial membrane1

Why does autoimmune disease (sometimes) follow viral infection?2

It’s a pretty well-known phenomenon, but a definite answer isn’t yet known — and of course there may not be a single answer, there may be multiple causes. We know that many autoimmune diseases seem to be triggered by some sort of infection or inflammation. A classic example is Guillan-Barre syndrome, which is a little more common (though still very rare) in people who have received certain influenza vaccines, but there are plenty of other examples.3 It’s not believed that the infection actually “causes” the disease, but rather that someone who already has a genetic predisposition to the autoimmune disease needs to have some kind of environmental trigger to have the disease actually kick in; and, very rarely, a viral or other infection will provide that trigger.

(The genetic predisposition is clear because, among other points, identical twins are much more likely to both get autoimmune disease than are fraternal twins; whereas the need for an environmental trigger is clear because even if your identical twin gets an autoimmune disease, you’re usually less than 50% likely to get it yourself. Note that I’m lumping together hundreds of different diseases into the “autoimmune” package, and the specific odds and so on differ for each one.)

OK, so if you have a genetic predisposition to autoimmunity — and let’s get more specific, the paper I’m looking at deals with multiple sclerosis (MS) — there’s a small chance that a viral infection will trigger that disease. One of the most popular models for this is “molecular mimicry”. Simplified: This is the notion that a viral protein looks, to a T cell, a little bit like a self protein. The viral protein appears in the context of infection, with its concomitant inflammation and tissue damage and so on, and the T cell is activated to it. The T cell wouldn’t be activated by the self protein because it hasn’t been seen in the context of inflammation before, but once over the activation hurdle the T cell is now able to attack the self protein, and this is autoimmunity.

TcR/MHC
T cell receptor (top) interacting with MHC

Molecular mimicry is an attractive model, but there’s not a lot of direct evidence for it.  Another possibility has been proposed for a while: Dual TcRs. Normally, T cells can only recognize a single target. This is by “design”;4 if the T cell can see two targets, it could get activated by one, and then attack the other, even if the second target was never present during inflammation. This sort of dual target recognition is obviously dangerous, and there are safeguards that mostly prevent it; but some T cells do sneak through with at least the theoretical potential for dual recognition. So what could happen here is that one TcR could be directed against the pathogen, and activate the T cell; then the other TcR, recognizing self, could run amok because it’s now on an activated T cell.

T cells with dual specificity do exist, at a fairly significant frequency (1-8%; at least one source claims as high as 33%, which seems much too high to me), but whether they actually do anything in autoimmunity is up in the air. This idea has been around for a while, but I don’t think there’s been much evidence for it happening naturally. In at least one case, where it was tested in an artificial system, dual TcRs did not seem to be responsible for an automimmune disease. 5

The most recent paper offers evidence that (in quite an artificial system) dual-specificity T cells are responsible for multiple sclerosis: 6

Our results demonstrate the importance of dual TCR–expressing T cells in autoimmunity and suggest a mechanism by which a ubiquitous viral infection could trigger autoimmunity in a subset of infected people, as suggested by the etiology of multiple sclerosis.

It’s an interesting and solid paper as far as it goes, but we’re left with the issue of this being a highly artificial system — mice with manipulated TcRs and manipulated autoimmune disease. Is this a real issue in natural autoimmunity and natural infections? This paper doesn’t really address that, but it does support the notion that it’s something to look more closely at.  (And again, different autoimmune diseases, or even different people with the same disease, may have altogether different triggers.  Maybe some people have molecular mimicry as the trigger while others have dual TcRs and other have who knows what.)


  1. By Raghuveer Parthasarath, then in the Groves lab[]
  2. Also, why are so many of my keyboard keys sticking together? An altogether easier question quickly answered by pointing to my kids “helping” me with my work while holding popsicles[]
  3. For a review:
    Fujinami, R. (2001). Can Virus Infections Trigger Autoimmune Disease? Journal of Autoimmunity, 16 (3), 229-234 DOI: 10.1006/jaut.2000.0484[]
  4. I.e. evolution.[]
  5. McGargill MA, Mayerova D, Stefanski HE, Koehn B, Parke EA, Jameson SC, Panoskaltsis-Mortari A, & Hogquist KA (2002). A spontaneous CD8 T cell-dependent autoimmune disease to an antigen expressed under the human keratin 14 promoter. Journal of immunology (Baltimore, Md. : 1950), 169 (4), 2141-7 PMID: 12165543 []
  6. Ji, Q., Perchellet, A., & Goverman, J. (2010). Viral infection triggers central nervous system autoimmunity via activation of CD8+ T cells expressing dual TCRs Nature Immunology, 11 (7), 628-634 DOI: 10.1038/ni.1888[]
June 17th, 2010

Dendritic cells that don’t prime

Langerhans cells in the skin
Dendritic cells in the skin (Langerhans cells) form a dense network of “sentinels” that act as first line of defense of the immune system.1

There’s a lot of interest in using dendritic cells as vaccines these days.  A paper in PLoS One2 offers a cautionary note.

Dendritic cells (DC) are the main cell type that drive T cells from their normal naive state to an active state.  In the naive state, a T cell can recognize its target, but doesn’t do anything about it; in the active state, the T cell does something, ranging from spreading inflammation to killing infected cells, and so on.  The DC is needed to bridge these states.  DC do many things, but at the simplest level they connect  the presence of an antigen (a T cell target, in this case) with the presence of something dangerous or abnormal — a pathogen, or tissue damage.

There are some conditions where we’d like an immune response, where DC don’t detect one or the other of their components (i.e. antigen or danger).  For example, there may be a situation that we know is dangerous, but where there’s  little evidence of “danger” for the DC.  A vaccine, for example, doesn’t want to deliver a huge amount of tissue damage, but we’d still like to get a strong response to an antigen.  For a natural situation, cancers are often ignored by the immune system even though there may be lots of cancer antigens, and one reason (of many) for this ignorance is that the DC may not perceive a lot of danger in the context of the cancer.

So why not take the DC out of the system, alarm them with some danger information in the test tube, load them up with antigen, and then return them to the body? That’s called a dendritic cell vaccine, and there’s fairly intense interest in the approach.

There’s been some success using this approach, but perhaps less than you’d expect from the biology as we understand it.

Several clinical trials conducted over the past decade have demonstrated that DC vaccines can prime and boost antigen-specific CD8+ T cells in humans. However, their clinical efficacy remains to be definitively demonstrated [6], [19], [20], [21]. The lack of success has been variously attributed to several factors: administration of relatively low cell numbers of DCs, suboptimal route of administration, improper antigen dose, poor choice of antigenic targets, unsuitable maturation state of DCs, and inappropriate frequency of injections. However, understanding exactly which of these concerns represent true problems may be difficult because little is known regarding the fate and function of ex vivo generated DCs after they have been injected 2

Dendritic cell

Yewdall et al asked what happens to DC after they’re given this course and returned to the patient (mice, in this case).  Their surprising conclusion is that the DC don’t work to prime T cells directly.  Instead, they have to hand off their antigens to other cells in the body that have never left:

Contrary to previous assumptions, we show that DC vaccines have an insignificant role in directly priming CD8+ T cells, but instead function primarily as vehicles for transferring antigens to endogenous antigen presenting cells, which are responsible for the subsequent activation of T cells. … This reliance on endogenous immune cells may explain the limited success of current DC vaccines to treat cancer and offers new insight into how these therapies can be improved. Future approaches should focus on creating DC vaccines that are more effective at directly priming T cells, or abrogating the tumor induced suppression of endogenous DCs. 2

As always in science, a single paper needs to be confirmed by others, so we won’t get too distressed until we see if other groups replicate this, and if it’s a universal truth or something specific to the particular system these authors were looking at.  (And, of course, this doesn’t trump actual evidence of efficacy for DC vaccines.) My own suspicion is that the work is accurate but limited, and there’s something about this particular system which prevented the transferred DC from being good primers; but as I say, I’d like to see some followup from another group.


  1. Tolerogenic dendritic cells and regulatory T cells: A two-way relationship. (2007) Karsten Mahnke, Theron S. Johnson, Sabine Ring and Alexander H. Enk. J of Derm Sci 46:159-167 doi:10.1016/j.jdermsci.2007.03.002 []
  2. Yewdall, A., Drutman, S., Jinwala, F., Bahjat, K., & Bhardwaj, N. (2010). CD8+ T Cell Priming by Dendritic Cell Vaccines Requires Antigen Transfer to Endogenous Antigen Presenting Cells PLoS ONE, 5 (6) DOI: 10.1371/journal.pone.0011144[][][]