Immunity, smell linked

Study finds that peptides that bind MHC act in vomeronasal organ of mice

Nov 5, 2004
Graciela Flores(

Peptides that bind major histocompatibility complex (MHC) class I molecules act as chemosensory signals in a region of the brain thought to be important in chemosensory communication, according to a study published in this week's Science. The peptides also acted as individuality signals in behavioral experiments.

"For many years, it has been suggested that there is a functional link between the immune system and the sense of smell," coauthor Frank Zufall of the University of Maryland told The Scientist. "These peptides are the first molecules to provide that link."

MHC molecules are well known for their role in binding foreign peptides and exposing them on cell surfaces for recognition by the immune system, but MHC peptide complexes can also be released into the extracellular space, reach the bodily fluids, and pass to other animals. Because MHC molecules and the peptides that bind them are quite unique for each individual, these peptides are good candidates for social recognition.

"The idea that there must be some kind of odor signal that is released by animals has been around for a long time," said Zufall. "The question was, 'What is the signal, and how it can influence social behavior?'"

In their search for the signal molecules, the researchers looked for ligands of MHC class I molecules that would activate neurons in the sensory epithelium of the vomeronasal organ, the secondary olfactory system. They used those molecules to map the neuronal activity and were able to identify particular subpopulations of neurons that responded to the different peptides in a genotype-specific fashion.

Zufall and his colleagues then tested the peptides' function as individuality signals in behavioral experiments. "In sexual behavior, mice gather a lot of olfactory information; they do a lot of sniffing of the face and the urogenital region," said Zufall. "If during a critical period of pregnancy, the female is exposed to another male, or to the smell of that male, she loses the pregnancy; that is known as the Bruce effect," which requires the mice to differentiate between individuality cues. When the researchers exposed pregnant mice to urine samples containing different MHC peptides, only those peptides corresponding to unfamiliar males triggered pregnancy loss.

Although the authors' "peptide hypothesis" provides a solid explanation for intraspecific communication, it does not rule out other explanations, such as those that propose that fragments of the MHC molecules, or the MHC molecules themselves, act as communication signals, or that bacteria living on the skin influence the body odor and deliver a message. "We haven't disproved any of those hypothesis," said Zufall. "But we have proved that the peptides were sufficient to induce an olfactory memory of an individual."

According to Lisa Stowers of the Scripps Research Institute, these results provide a nice, solid starting place for further research in this field. "This is a potential piece of the whole puzzle of how an animal is sensing its environment and responding appropriately," said Stowers. "Whether these molecules are acting in coordination with small molecules and with neurons that may be outside the vomeronasal organ will have to be determined."

Charles Wysocki, of the Monell Chemical Senses Center, also praised the study. "This is a beautiful piece of multidisciplinary work," he said. "Their work is showing that the vomeronasal epithelium is responding to these peptides, but we have recently published a paper showing that the vomeronasal organ is not necessary to discriminate MHC types in mice," he said. "Now we have to put these two pieces of information together and make sense of them."