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[]