The role of the MHC proteins in our Mate Selection – An Insight into the Immune System #4

How our Mate Selection is directed by our Immune System

If you have not seen my previous articles on this topic, I am glad to provide them to you here:
Immune System #1 - Innate Immunity
Immune System #2 - Adaptive Immunity
Immune System #3 - Structural Aspects

In this post I will mainly focus on the Major Histocompatibility Complex (or MHC), which I already mentioned in earlier posts. But now it is time to have a closer look at it, since I want to explain the following saying:

Image Source - (Text added)

MHC proteins bind intracellularly produced peptides and present them on the cell surface. The immune system is alerted to the presence of a foreign protein by interaction of a T-cell receptor with a MHC protein that binds a peptide derived from a foreign protein. MHC proteins fall into two classes, with similar structures and functions:

Humans express six Class I and a somewhat higher number of Class II MHC proteins. The overall system is highly polymorphic, with 50 -150 alleles per locus and six loci in total.
For clarification: Alleles are variant forms of given genes and "locus" names the physical place where a gen is located within the genom.

All this gives a decent number of different MHC proteins, but how can these recognize and bind an almost unlimited number of antigens? To understand this one has to have a look on the structure of the MHC:

Class I MHC consists of a heavy membrane-spanning (360 amino acids) and an attached light chain (99 amino acids). The light chain β2m (red) is homologous to the constant immunoglobulin domains and has essentially the same 3D-structure.
(see Immune System #3 - Structural Aspects)
The extracellular portion of the heavy chain forms three domains (α1, α2 and α3), each comprising about 90 residues.
Again, α3 shows sequence and structural similarity to the constant immunoglobulin domain, therefore α3 and β2m also associate in a similar fashion as the constant domains in IgG.

The second region, which forms the antigen-binding site, consists of α1 and α2. (top part)
So let's have a closer look on this one:

The Structure of the antigen-binding site in Class I MHC

Starting from the N-terminus, each domain forms a 4-stranded antiparallel β-sheet (in the above and below image illustrated in light green and blue). The two β-sheets associate with each other by hydrogen bonding in an antiparallel fashion, forming an extended 8-stranded "floor". This floor is flanked by two long α-helices on either side - forming a large cervice which constitutes the antigen binding site - as shown in the top down view:

Class II MHC proteins do have differences to the Class I MHC ones: They do have two equally sized chains of about 360 residues and the two domains that constitute the antigen binding site (α and β respectively) are on different chains. However, the overall tertiary domain structures are similar to those seen in Class I. Hence for our considerations they can be discussed together. For a better understanding of the following collection of facts about the peptide binding to the MHC protein have also a look at the subsequent illustration:

• In Class I MHC, the N- and C-termini of the bond peptide are buried inside the crevice whereas central regions are bulging out from the cleft.

• Conserved residues form hydrogen bonds to these termini.

• This interaction limits the length of peptides that can bind to Class I MHC to 7-10 residues and allows the binding of longer peptides (> 10 residues) to Class II MHC.

Knowing this the broad specificity of MHC can be explained:
Ultimately it is brought about by numerous contacts with the main-chain of the peptide in a peptide-sequence independent way and by conformational flexibility of the binding site that allows binding of different peptides. Thus the mechanism of antigen recognition by MHC proteins differs from that of antibodies!

But how do MHC proteins influence our Mate Selection?

Recall that T-cell receptors only recognize antigens when they are presented with MHC protein. In other words, destruction of the pathogen depends on the efficiency of this binding process. If all individuals of a vertebrate species had an identical set of MHC proteins, pathogens with epitopes that bind poorly to MHC protein would escape detection by the T-cell receptor and hence could lead to the obliteration of the whole species. Natural selection therefore favors a large variation of MHC proteins in order to make the species less vulnerable to infections.

Astonishing discoveries:

A. In the 1970s, Yamazaki & colleagues observed that inbred laboratory mice were more likely to mate with mice having dissimilar MHC genes. Findings were later confirmed by Potts in a more natural setting.

B. When newborn male mice are placed together with foster mothers of a different MHC strain these male mice would later avoid females having the same MHC genes as their foster mother's. This suggests that exposure during development, rather than some innate MHC mate-choice program, appears to be at work!

C. Studies with mice have stimulated an investigation of mate choice in the Hutterite population in North America (C. Ober, University of Chicago). Hutterites marry only among each other and usually to members of other colonies. As a result, the Hutterites are relatively inbred. Typing of 411 couples in Hutterite communities revealed that they had much fewer MHC genes in common than expected in an inbred population. Further analysis revealed that if spouses had MHC genes in common, they were derived from the paternal side for both wife and husband.

D. Mice and rats can distinguish the urine and body odor of fellow creatures caged in the same way, fed the same food, and bred to be genetically identical in all but their MHC genes. Remarkably, even humans can smell the difference in body odor, urine and feces among mice of various MHC types!

E. In a human study (Wedekind, U of Berne, 1995), women were presented with T-shirts saturated with body scent of men with various MHC types. The women "preferred" the T-shirts of men with MHC types unlike their own. The preferred "smell" was also identified as their current partners, suggesting that odor has significant influence on their real-world choices.

Conclusions:

• Men and women avoid partners with MHC genes resembling their mother's.

• In agreement with these findings, it was also shown that for females, how someone smells is the single most important variable in choosing a partner!

I hope you enjoyed this post! If you have any questions do not hesitate to ask them in the comments. Also if you do have any suggestions for future scientific topics that should be presented, just let me know. Maybe my expertise covers the suggested topic and I can present you some interesting insights.

Best,
mountain.phil28

References:
Information and non-direct-cited images are taken from
"Molecular Physiology" lectures at the TU Graz.