Basic Information

Name: Manfred Milinski
(Feb 1950–）

Birth
Location: Oldenburg, Germany

Title: Professor

Affiliation: Max Planck Institute for Evolutionary Biology

Honor: Unknown

The Mechanism of MHC Odor Signaling

Manfred Milinski

Immune genes of the vertebrate MHC vary among individuals. Each individual collection is optimally diverse to provide resistance against some infectious diseases but not too diverse to cause autoimmune diseases. MHC-dependent mate choice aims for optimally complementary MHC alleles. Each potential partner signals through body odor his/her MHC alleles. Identifying the signal molecules was a long-lasting puzzle solved only recently after many deviations as described. Commensal microbiota which are controlled by the individual MHC genes differ among individuals but cannot provide the much sought after.

• major histocompatibility complex
• signaling
• olfaction

1. Introduction

Immune genes of the Major Histocompatibility Complex (MHC) are by far the most polymorphic genes in vertebrates. Only one or a few different MHC alleles provide resistance to a specific parasite [1,2]. Each individual’s mix of MHC alleles determines its specific resistance against current infectious diseases [2]. This fact invites hypotheses on MHC-dependent mate choice. However, it was inconceivable until 1975 that an individual’s MHC genes organize its mate choice decisions. This year technicians at the Sloan-Kettering Institute in New York made a remarkable observation: “The technicians looking after these mice reported that the male and female of dissimilar H-2 type appeared to consort with one another to the relative exclusion of the female whose H-2 type was the same as the male’s” [3]. Starting with Yamazaki et al. [4] numerous studies, mostly with inbred strains of mice, showed that actual mate choice favors MHC dissimilar individuals e.g., [5,6,7,8,9,10,11,12,13]. MHC-dependent mate choice was demonstrated also in other vertebrates such as rats [14,15,16,17], birds [18,19,20,21,22,23,24,25,26,27], fish [28,29,30,31,32,33,34,35,36,37], reptiles [38] small mammals [39], primates [40], and humans [41,42,43,44,45,46].

This review follows the history of studying MHC-dependent mate choice. Because most of the early experiments were performed with mice, later followed by stickleback fish, insights and ideas focused to some extent on these models and thus had limitations for being generalized. It is, however, convenient to describe the history of understanding mechanisms and functional consequences of MHC-dependent mate choice in one or two finally well-studied and understood systems rather than including the great variation among species right from the beginning. I found it convincing how the various parts of a system made sense as predicted by immunological theory. It could be the ‘null system’ which needs to be extended to cover natural variation.

One sensory modality that transports the information about an individual’s MHC was revealed again in mice: odor. The choice between urine odor from MHC similar and dissimilar mice in a y-maze favored MHC dissimilar individuals e.g., [5,47,48,49,50,51,52,53,54]. Thus, odor transmits the MHC signal and the choosing mouse knows her own MHC otherwise she could not prefer ‘dissimilar’. At the time some MHC researchers were skeptical. ‘Some immunologists resist the idea that MHC genes could themselves specify odors. In part, this is because there has been suggested no plausible mechanism by which these genes, which code for cell-surface proteins, could also specify differential body odor’ [55,56]. A number of studies revealed mate choice that was based on odor, in rats [14,15], fish [29,30,31,32,33,34,36], reptiles [38], birds [24,25,26], small mammals [57], and Humans [42,43,44,45,46,58]. Thus, there must be a mechanism. Because the polymorphic MHC genes of the vertebrate immune system are highly conserved and at least 450 my old [59], the olfactory signaling and recognition system may probably be similar in all jawed vertebrates.

2. The Microbiota Signalling Hypothesis

The puzzle of the origin of the odor and of its composition took a long time to be solved. One possibility could be that populations of commensal microorganisms generate differential odorants whose composition eventually reflects MHC diversity [49]. The MHC class II gene family may be a candidate for adjusting diverse and host-specific microbiota. MHC genes may affect the composition of the microbial community of symbiotic bacteria through the elimination of specific bacterial species in an antigen-mediated fashion; thus, an individual’s MHC genotype might be able to shape the composition of symbiotic bacteria that can survive on or inside the host. The microbial communities that result potentially influence host odor [24,26] as well as host fitness [60].

Bolnick et al. [61] showed that MHC IIb polymorphism is correlated with variation in gut microbiota among individuals within a single population of three-spined sticklebacks. Individuals that had more divergent MHC motifs carried less diverse microbiota. However, MHC explained roughly only 10% of microbial variation [61]. The primary source of body odor in birds is preen oil [25,26]. Similar preen secretion chemicals correlate positively with MHC-relatedness [25]. In behavioral discrimination tests, kittiwakes and blue petrels can assess MHC similarity on the basis of odor [25]. When song sparrows (Melospiza melodia) were presented with preen oil from conspecifics of opposite-sex, both sexes preferred odor from MHC- dissimilar to MHC-similar birds in a two-choice design [26]. According to the authors, song sparrows can discriminate MHC similarity of potential mates by using preen oil odor. Similarity at MHC is thus a predictor of similarity in the composition of preen oil [62]. This relationship may be hypothesized to be mediated by symbiotic microbes. The MHC genotype, the microbial communities in preen glands, and the chemistry of preen oil was characterized in song sparrows [62]. Pairwise MHC similarity predicted similarity of microbiota in preen glands. However, the overall similarity of microbes did not predict similarity in the chemistry of preen oil.

Obviously preen oil contains an MHC-dependent odor signal. Because preen oil composition was related more strongly to MHC genotype than to preen gland microbiota overall, the authors suggested the following: the effects of MHC on the composition of preen oil are not facilitated primarily through microbiota in the preen gland [62]. Instead, the MHC genotype may affect host odor more directly [62]. Although microbiota within preen glands correlate with MHC, which might be just MHC’s immunological action of regulating bacteria, it is not clear whether microbiota contribute to MHC dependent odor of preen oil.

The microbiota hypothesis experienced almost continuous ups and downs that read similar to a fascinating criminal story: Yamazaki et al. [49] suggested that populations of commensal microorganisms may generate differential odorants; their composition maybe somehow adjusted to MHC diversity. In the same publication, they provide a direct test of the hypothesis by excluding microbiota. If microbiota are necessary for producing the MHC-dependent odor signal, germ-free mice should not produce it. This hypothesis was tested: Mice are trained in a Y-maze system to distinguish the urinary odors from MHC-congenic mice. Mice could also easily be trained to distinguish the urines of MHC-congenic mice that had been raised germ-free. Also, mice that had learned to distinguish the urines of conventionally maintained MHC-congenic mice were shown to distinguish readily the urines of germ-free congenic mice. Thus, MHC-determined odor types do not depend on microorganisms generating odorants [49]. In the same year, Singh et al. [63] published the finding that rats lost their individuality odor when reared in a germ-free environment. Male rats were reared in a germ-free environment after being born by the cesarian section. A habituation-dishabituation test revealed that urine from the germfree rats was not discriminated, whereas urine from rats of the same strain that were housed conventionally could be discriminated. When urine from germfree rats was collected, after they had been moved to a conventional animal house after recolonization with commensal flora, it was discriminated against. This indicated that bacteria had an essential role in determining the urinary odors of MHC congenic rats. ‘We would predict that bacteria may control the production of MHC-specific odors in mice and other species as they do in rats’ [17].

The results of Yamazaki et al. [49] and Singh et al. [17] are at variance. Singh [63] offers a solution for the discrepancy. “We suspect that the differences between the results obtained lies in the methodology used, ’habituation-dishabituation’ relies on the odor stimulus being different enough for it to be interesting to the responder animal, leading to its dishabituation, while the motivation to detect a difference using the ‘training-reward’ system is much greater: the mice are thirsty and detecting the difference allows them to drink. Thus, the residual MHC-related odors (derived from normal metabolic processes, other than gut flora) that remain in germ-free urine are more likely to be detected by the trained mice, while untrained mice may not have the ‘motivation’ to discriminate between the germ-free urine samples.”

Yamazaki et al. [56] comment on ‘this apparent contradiction’ that the clear key are differences in methods. They assume that the relevant odorants are still expressed in germ-free animals but in smaller amounts such that they fail in the habituation paradigm to motivate non-contingent investigation. ‘If this is so, then the hypothesis that MHC genes specify odor by controlling commensal microflora cannot be true’ [56].

If the ‘microbiota signaling hypothesis’ is to be revived, some proximate and functional questions need to be answered, for example [64]: If we consider an info-chemical X that animal-A produces and which alters the behavior of animal-B, to demonstrate that the microbiota in animal-A synthesize info-chemical X, three lines of evidence are required: (i) Some microbiota in animal-A can synthesize X. (ii) If the microbiota from animal A are eliminated, both the loss of X and the loss of the behavioral trait of animal-B results; and (iii) interaction with microbe-free animal-A that has been supplemented with the info-chemical X revives the behavior of animal-B.

If these stringent conditions are fulfilled, it needs the study of the evolutionary processes that facilitate the origin and also the persistence of communication that is microbial-mediated, rather than chemical signals that the animal host synthesizes itself, avoiding conflict between microorganisms and the animal host [63,64]. Before we come back to microbiota we discuss what was proposed next.

3. The ‘Carrier Hypothesis’

Several ideas assumed that MHC molecules are the carriers of the specific info chemicals. After an infection, the host’s cells contain foreign proteins which are degraded by proteasomes into small pieces, about nine amino acids long, called peptides. In order to inform the T lymphocytes outside the cell, the peptides need to be bound and transported through the cell membrane and presented to T lymphocytes. This is the task of MHC molecules if the peptide fits into the binding groove of an MHC molecule by its ‘anker amino acids’ in specific positions of the peptide [65], irrespective of whether it is a foreign or a self-peptide. Each of an individual’s few MHC alleles has its specific binding groove to bind only specific peptides, although examples of promiscuous peptide binding exist [66,67]. To avoid auto-immune diseases, T lymphocytes have been selected in the thymus to recognize only foreign peptides to induce an immune response [68]. Thus, the broader the spectrum of one’s MHC alleles, the more infectious diseases can be presented to and attacked by the immune system suggesting mate choice for MHC dissimilar partners. This allows each MHC molecule to bind and carry only chemicals that transport information of the MHC molecule’s individuality expressed by its peptide binding groove. From collecting all the peptides transported by the MHC molecules of an individual it would be possible to deduce the nature of that individual’s MHC alleles, i.e., its MHC genotype. Thus, peptides would be ideal info-chemicals constrained by their low volatility.

However, other info chemicals carried by MHC molecules were suggested. Evidence for volatiles that have distinctive patterns according to MHC type has been reported [54]. Carboxylic acids have been found, in behavioral active dimethyl ether extract of acidified urine, that distinguish male mice that differ only at their MHC [55]; these chemicals probably have a critical role when MHC-congenic mice are discriminated by olfaction [55]. It is suggested that the most likely mechanism for this could be that circulating odorants are bound selectively by soluble MHC gene products themselves; these have presumably lost their bound peptide before. Then the odorants are released to a minimal degree in serum and probably more extensively during renal processing and excretion. It is suggested that these odorants are likely the volatile acids that have been identified or precursors of them [56].

The fact that MHC class I molecules can associate selectively with small molecules could also suggest a way for transporting a unique mixture consisting of volatile, endogenous metabolites to urine from the blood by MHC glycoproteins [16]. Although each individual has a similar metabolic pool, this mixture would be unique to the transporting particular MHC molecule. An individual-specific odor would be imparted to the urine. The postulated volatile molecules need to be identified [16]. Maintaining the microbiota hypothesis, Singh et al. [17] propose that the excretion of class I molecules has an important role in individual odor to be determined in the urine. Bacteria are considered to be an essential source of the body’s pool of odorant molecules by which individuals do not vary. A mixture of odorants is selected by an MHC molecule from the body pool. The MHC molecule acts as a carrier to deliver the cocktail to the urine. This is assumed to be analogous to the manor of MHC molecules binding and presenting immunogenetic peptides to T lymphocytes [17]. ‘The ‘carrier hypothesis’ represents the simplest explanation of the mechanism whereby the MHC confers odors of genetic individuality’ [64].

However, Singh [69,70] dismisses the microbiota hypothesis: The intimate linkage of MHC genotype with the urinary odor was argued to be indirect and to reflect the immune response that responds to commensal bacterial flora causing individual MHC types to be associated with unique flora. The volatile odorants excreted were assumed to be secondary metabolites that are derived from these organisms. This hypothesis seemed unconvincing a priory because the types and relative numbers of commensal bacteria are required not to vary over time, which is not true [71]. According to three studies, immune regulation of commensal flora is not needed for the determination of MHC-associated odors [49,72,73].

Singh [69,70] again supports the carrier hypothesis in more detail. He argues that MHC molecules are not likely to be the odor components because of their size and missing vapor pressure. However, MHC molecules might be in an allele-specific association with smaller molecules for transporting them to the urine [16,69]. Thus, from a pool of metabolites, a unique mixture of volatiles could be selected, in which, commensal flora could take part [17]. After transport, a unique odor that is MHC specific would appear in the urine. A mechanism might work by which MHC molecules each pick up a unique mixture of volatiles in their binding groove to be transported to the urine as an individuality marker.

MHC-associated peptides are cleared into the circulation, undergoing further fragmentation. The release of any bound peptides allows the now empty platform to bind a unique mixture of odorants, to be transported to the urine where they are further degraded to molecules that make up an odor that is MHC specific. “The nature of the specific odorant molecules that are bound to soluble class I molecules is unknown, although carboxylic acids may be one source” [54].

“The problem with the carrier hypothesis is that it is difficult to imagine how binding properties of MHC molecules might be converted from being hydrophilic peptides-binding molecules to hydrophobic aromatic-binding molecules” [52]. Even if one would agree with the “empty platform” being able to bind a cocktail of volatiles, how could the released molecules of the ‘cocktail’ transport the information content of the specific sequence of amino acids mirroring the binding cleft of the MHC molecule? A receptor in the receiver animal needs to catch and reassemble the loose volatile molecules into the original sequence to extract the individuality of the source MHC molecule. It needs the study of the mechanisms of the receptor side. We are not yet informed about the nature of the involved volatile molecules. No qualitative differences in volatile compounds have been found in association with MHC types by any investigation except one. However, for volatile metabolites, patterns or relative ratios vary in relation to MHC types, but in a way that is inconsistent and complex [74].

4. Mate Choice Optimizing MHC for the Offspring

Sex would not be needed for maximizing resistance if everybody has the whole spectrum of MHC variants. However, with each MHC molecule added to an individual’s repertoire, T cell lines that react to self-peptides bound by that MHC variant must be removed to avoid auto-immune diseases. Thus, an optimal number of different MHC molecules per individual is predicted by theory, based on immunological results, instead of a maximum MHC diversity [77,78]. It could be optimal for humans and mice to have their low number of MHC loci for balancing an increased number of foreign peptides to be presented and an increased number of T cells removed from the original repertoire [68,76]. The consequence is an optimal (intermediate) number of different MHC alleles per individual, enough to defend against many natural diseases and not too many to keep a ‘reasonable’ collection of T cell clones [77–79]. The immunogenetic optimum found in nature was published first [29,85] and experimentally proven on three-spined sticklebacks [86]. This individual optimum maximizes reproductive success [87] and increases survival under natural conditions [88,89]. Also, for other vertebrates, e.g., birds [21,22,89], trout [37], and voles [39] optimal individual MHC diversity was demonstrated. Experimental mate choice studies found that female three-spined sticklebacks prefer the odor of a male that signals that it possesses MHC alleles that combined with the female’s come close to the predicted individual optimum [29–31,90].

5. The ‘MHC Peptide Hypothesis’

MHC ligand peptides fulfil the requirement that the exact information of the sender’s MHC alleles is transmitted by his odor signal [91,92]. MHC molecules are specialized to be carriers of peptides and devices to display them. The binding specificity of the MHC molecule is mirrored by the composition of the peptide. The ‘MHC peptide hypothesis’ assumes that smelling the peptide ligand (‘the key’) informs about the MHC protein (‘the lock’) [93]. An individual’s underlying MHC diversity can be derived from the peptide ligands that he emits. Peptides interact with receptors of the olfactory system [94] and activate olfactory sensory neurons even at low concentrations [95,96]. Individual neurons each respond to one specific MHC ligand peptide only. The peptide’s anchor residues that allow binding to ‘its’ MHC molecule define this specificity. The olfactory neurons react exactly to those parts of the peptide that define the MHC molecule’s specificity of binding the peptide. ‘The role of MHC peptides as signals of individuality appears to be evolutionarily conserved’ [91]. As experimental mate choice studies found female three-spined sticklebacks prefer the odor of the male that signals the possession of MHC alleles that combined with the female’s approach to the individual optimum, as has been predicted [29–31,90].

6. MHC Ligand Peptides Are Used in Actual Mate Choice Decisions

It should be possible to manipulate the information of the signal by adding further peptides, if peptides naturally signal via odor revealing the MHC alleles of a male. A female stickleback prefers a male that offers by scent MHC alleles that optimally complement her own alleles [90,99]. Thus, a suboptimal male’s attractiveness should be increased and an optimal, as well as a super-optimal male’s attractiveness, should be decreased if the same four synthetic MHC peptides are added to either male’s natural signal. Choice between spiked and un-spiked water from the tank of the same male revealed that the peptide side was preferred when the pair had a combined diversity that was below the optimum. The spiked side was, however, avoided when the pair was above or at the optimum [30]. It can well be that MHC peptides are part of the natural perfume-like signals in other vertebrates including humans.

7. MHC Peptide Ligands as Olfactory Cues in Humans

When human participants in psychometric tests were asked their decision whether what they smelled was perceived as ‘like themselves’ or ‘like their favorite perfume’ [58], they preferred their modified body odor, when their own synthesized ‘self’ peptides were offered, to modification by synthesized ‘nonself’ peptides (from another participant). Thus, in humans MHC peptide ligands may function as part of body odor. These findings remind of results showing that humans that share specific MHC alleles share also a similar preference for the same natural ingredients of perfume [100]. Diverse peptide mimics may be contained in perfumes. As revealed by a ‘functional magnetic resonance imaging’ study, self-peptides allele-specificly activated a region in the right middle frontal cortex. This demonstrates the human sensory facility to recognize odor cues that are specific to MHC [58]. As was shown in mice [96], peptides may invoke sensory neurons in the main olfactory epithelium. However, activation of the brain through exposure to peptides does not mirror the precise chemical structure of the peptides. It rather shows their qualities of ‘self’ or ‘nonself’ in relation to the MHC genotype of the individual. An internal reference for the genotype of MHC reminds us of a similar finding in mice [94] and sticklebacks [30]. As is the case in mice and fish, the sensory evaluation of the diversity of MHC through recognizing structurally diverse MHC ligand peptides, may be part of human MHC-dependent behavior.

8. Can Signaling Microorganisms Help Optimizing?

Individuals of wild sticklebacks that possess more divergent MHC motifs harbored less diverse microbiota, although their MHC explained only about 10% of microbial variation [61]. To estimate an optimum from microbial variation would thus be extremely vague. Furthermore, microbial variation fluctuates with diet and many other environmental influences. Preferring a mate with more diverse microbiota would allow a female to select the more MHC dissimilar mate. Thus, for choosing ‘dissimilar’ using potential signals from microbiota would, in principle, suffice. For selecting the optimally MHC complementary mate, however, it needs ‘smelling’ exactly which MHC alleles a potential mate habors. A male would need to have exactly only those microorganisms that signal his mix of MHC alleles. He has, however, vastly more different microorganisms than this small number. For optimizing MHC using potential odor from microorganisms thus cannot work.

9. A Failed Revival of the Microbiota Signaling Hypothesis

Schubert et al. [101] reviewed 577 publications to find how the MHC might mediate social odor via the microbiota community, for example, to allow for MHC-dependent mate choice. However, none of the 577 studies found the odor to be a social signal. Their extensive review of complex immunological networks, potentially affecting microbiota and odor through various pathways, did not solve the problem of how the microbiota of an individual could signal the possession of exactly his MHC alleles to allow for optimal mate choice. The authors nevertheless “hoped that their review stimulates advances in the investigation and understanding of this key pathway for social communication” [101]. A response [102] to a commentary [103] that pointed to gaps in their argumentation neglected responding to the main criticisms [102]. The authors, on the contrary, reiterate that although “an established mechanism that provides allele-specificity has already been identified: peptide ligand-based odor signals” [101], “multiple signaling mechanisms that transmit the same information are useful” [101]. Two counter-arguments can be listed: (i) Microorganisms are not able to transmit the same information (see above), and (ii), if highly conserved peptide signaling would be joined by a microbiota signaling mechanism [91], if microbiota could actually do the signaling, this additional second mechanism cannot evolve because it does not increase the sender’s performance that is achieved with the primary mechanism no fitness gain to achieve, no further evolution possible. No need for “keeping alternative hypotheses on the table” [101].

10. Egg Chooses Sperm with Regard to MHC

Female choice of a mate that offers a complementary whole MHC genotype allows only for a poor approach of the best match. A maternal and a paternal haplotype would be randomly combined. Resulting from meiotic segregation among oocytes and sperm, the genotype is phenotypically unpredictable. Ultimately this determines the genotype of the offspring. The lottery of random fusion of gametes can easily result in nonoptimal combinations of MHC haplotypes. If, however, the egg chooses and prefers the more complementary of the two sperm haplotypes of a male, it would have an offspring that is closer to the optimum MHC diversity. That sperm may select for MHC complementarity has been hypothesized [104–108]. MHC expression on the sperm surface was found by some studies [2,109].

How can the egg decide? Cross-talks during sperm–egg interaction, studied in mice, clearly showed expression of MHC class II antigen on the post-acrosomal membrane of the sperm head [110,111]. The micropyle of fish eggs, which is an opening in the coat of the egg through which sperm enter the egg for fertilization, apparently carries specific molecules [113]. These are active in attracting sperm toward the opening of the micropyle [114,115]. Such observations offer a potential way to preferentially guide MHC-complementary sperm to the micropyle opening. There is still a gap to be filled.

11. Functional Tests Implying Choice of Gametes

When eggs could choose between sperm derived from MHCidentical and from MHC dissimilar males, results were mixed [115–118]. When congenic laboratory strains of mice were crossed, parental MHC haplotypes combined non-randomly. The process, however, was affected by the infection with mouse hepatitis virus of the parents [119,120]. ‘Decisive experimental evidence for oocyte selection of specific sperm haplotypes is still elusive’ [121].

12. Oocyte Selection for Sperm Haplotype to Optimize MHC of the Zygote

When eggs of a female stickleback were exposed simultaneously to equal volumes of sperm from two males, the result was four male haplotypes available for fertilization of each egg-haplotype. This mimicks a scenario with a sneaking neighbor [122]. Ranking the four sperm MHC haplotypes available for fertilization of each egg-haplotype according to their success in fertilization, the most successful of the sperm haplotypes was closer than the least successful one to the mean MHC divergence of the population, which approximates the optimal individual MHC divergence. Furthermore, only the two sperm haplotypes within each male were compared to avoid interaction with sperm traits, e.g., velocity or density. For each individual male sperm traits should be the same. Again, the zygote produced with the more successful sperm haplotype of two was closer to the MHC optimum than the zygote formed with the less successful one [122]. Again, the zygote produced with the more successful sperm haplotype of two was closer to the MHC optimum than the zygote formed with the less successful one [122]. Thus, eggs selecting MHC-compatible sperm prefer the best combination avoiding the lottery of meiosis, as shown in sticklebacks. The signal mode is not yet known, it could be odor again.

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