Trends in Neurosciences
Volume 29, Issue 2, February 2006, Pages 100-107
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MHC peptides and the sensory evaluation of genotype

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Social interactions, such as finding and identifying a mate, often rely on the ability to sense molecular cues carrying information about genetic relationship and individuality. We summarize recent evidence for an unexpected mechanistic link between the immune and olfactory systems in enabling this identification process. In addition to their established role in the immune response, peptide ligands of major histocompatibility complex (MHC) molecules constitute a previously unknown family of social recognition signals detected by specific subsets of sensory neurons in the mammalian nose. This sensing of MHC peptides can be viewed as a form of functional genome analysis by the nose. Behavioral studies in mice and fish show that MHC peptides are accepted as olfactory cues that influence mate choice decisions and selective pregnancy failure. These findings provide a molecular mechanism by which an individual can sense the composition and compatibility of vital immune system molecules of a conspecific, with direct consequences for social behavior.

Introduction

An important advance of recent years has been the identification of several evolutionarily conserved genes that are required for basic aspects of social behavior [1]. Together, such studies have established that social behavior often has a genetic basis. For instance, neurotransmitters and their receptors are involved in the establishment and maintenance of social hierarchies and dominance interactions [2], certain transcription factors are involved in vocal learning and vocalization in birds and primates [3], particular neuropeptides function in regulation of parental care in various species [4], and the ion channel TRPC2 is essential for the display of aggression in mice [5].

Chemical communication among individuals of the same species is a versatile and widely used means of social interaction. It can be conceptualized as a three-component system (Figure 1) that involves production, transmission and perception of semiochemicals – that is, chemical signals used for communication. Importantly, these signals are probably used in a combinatorial, hierarchical and context-dependent manner to enable animals to adjust their behavioral responses to specific needs. Chemical signals are produced via different metabolic pathways; consequently, these signals have a wide variety of chemical structures, including such diverse molecules as steroid and peptide pheromones 6, 7, 8, 9. Additionally, the production of such signals might be either constitutive or inducible (e.g. depending on gender or maturation stage), which could further enhance the information content of these signals. The chemical nature of these signals is probably constrained for reasons of efficient transmission and specific function: chemosignals can be nonvolatile or ephemeral and might (e.g. [10]) or might not require specific carriers. Therefore, with respect to different signals, transmission can be either indiscriminate or selective. On the receiving end of chemical communication systems, the olfactory system has a crucial role in the evaluation of chemical signals. Olfactory recognition can be broadly or finely tuned, depending on the particular nature of a given chemical and its role in the communication process.

Section snippets

Signals of individuality carry genotypic information

Social interactions often require information about genetic relationship (individuality), and these signals are particularly important for mate choice decisions and post-mating behaviors such as kin recognition. How can we define the functional properties of chemical signals carrying information about individuality? Signals of individuality are probably structurally polymorphic molecules that are superimposed on other structurally invariant species-specific signals. In any case, signals of

MHC system and signals of individuality

It was shown almost 30 years ago that genes at the MHC locus influence behavioral decisions in the context of social recognition in mice 15, 16. Subsequently, it became clear that MHC genes have similar roles in fish 17, 18, birds [19] and humans 20, 21. MHC genes are among the most polymorphic multi-gene families known 11, 12. Historically, they have been investigated for their role in cellular immunity, because they enable intracellular protein synthesis to be monitored on a near real-time

Modification of behavior by MHC peptide ligands

On the basis of these theoretical considerations of the information content of MHC–peptide complexes (Box 1), MHC peptide ligands themselves can be considered the most likely candidates for individuality signals (Figure 2). This hypothesis has recently been tested in two model systems, mice [25] and fish [26] (Table 1). Whether MHC peptides could function as signals of individuality in the context of pregnancy block was investigated in mice [25]. In this paradigm (Box 2), recently mated female

Neurophysiological basis of peptide recognition

The olfactory assessment of MHC peptides at the level of individual neurons was examined in mice [25] (Figure 3). The mouse olfactory system is divided into at least two anatomically distinct organs, the vomeronasal organ (VNO) and the main olfactory epithelium (MOE) [31]. Although initially viewed as functionally non-overlapping, with the VNO being responsible for detection of nonvolatile molecules and the MOE being responsible for detection of volatile chemicals, this strict distinction has

Integration of signals of individuality with other chemical signals

Chemosensory cues recognized by the VNO and MOE, although initially processed separately 31, 36, converge at the level of the amygdala 31, 37. Thus, the neuronal hardware exists to regulate behavioral responses mediated by the two systems both separately and coordinately. It has also become clear that innate behavioral responses are not the only ones regulated by the VNO: in the pregnancy-block phenomenon, the behavioral outcome depends on prior olfactory memory formation (i.e. olfactory

Encoding and decoding signals of individuality

How specific is an individuality signal based on the use of MHC peptide ligands? Addressing this question requires further consideration of the information content of MHC–peptide complexes. Peptides are bound by the MHC molecules through interactions of two to three amino acid side chains with complementary pockets in the binding groove of the MHC molecule 11, 12 (Figure 2; Box 1). If all 20 common amino acids were to occupy these two or three anchor residues, ∼400–8000 different peptide anchor

Functional genome analysis by the nose

In summary, the assessment of an individuality signal by the nose can be viewed as a sensory mechanism to determine genome composition. The recently discovered role of MHC peptides in this process described here reveals an unexpected mechanistic link between the immune and nervous systems in processing genotypic information. However, it appears that the immune and nervous systems decode the information contained in the structure of MHC peptides in a fundamentally different manner. Because the

Conclusion, future prospects and questions

As indicated by the evidence summarized here, the role of MHC peptides as signals of individuality appears to be evolutionarily conserved. This will prompt further studies using various animal models – including humans – to determine whether they employ a similar sensory mechanism (Box 3). With their vast structural repertoire, the MHC peptides represent the first large family of social recognition signals detected by the nose, but it is important to note that they might not be the only

Acknowledgements

We acknowledge the contributions of Trese Leinders-Zufall, Peter Brennan, Patricia Widmayer, Prashanth Chandramani S., Andrea Maul-Pavicic, Martina Jäger, Xiao-Hong Li, Heinz Breer, Manfred Milinski, Sian Griffiths, K. Mathias Wegner, Thorsten B.H. Reusch, Annette Haas-Assenbaum, Marc Spehr and Kevin R. Kelliher to the original research work carried out in our laboratories. Kevin Kelliher also provided valuable comments on the manuscript. Financial support from the Max-Planck Society and the

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