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Structural requirements for the activation of vomeronasal sensory neurons by MHC peptides

Nature Neuroscience volume 12, pages 1551–1558 (2009)Cite this article

Abstract

In addition to their role in the immune response, peptide ligands of major histocompatibility complex (MHC) molecules function as olfactory cues for subsets of vomeronasal sensory neurons (VSNs) in the mammalian nose. How MHC peptide diversity is recognized and encoded by these cells is unclear. We found that mouse VSNs expressing the vomeronasal receptor gene V2r1b (also known as Vmn2r26) detected MHC peptides at subpicomolar concentrations and exhibited combinatorial activation with overlapping specificities. In a given cell, peptide responsiveness was broad, but highly specific; peptides differing by a single amino-acid residue could be distinguished. Cells transcribing a V2r1b locus that has been disrupted by gene targeting no longer showed such peptide responses. Our results reveal fundamental parameters governing the response to MHC peptides by VSNs. We suggest that the peptide presentation system provided by MHC molecules co-evolves with the peptide recognition systems expressed by T cells and VSNs.

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Figure 1: V2r1b-expressing VSNs have transient Ca2+ responses to MHC peptide ligands.
Figure 2: V2r1b-expressing VSNs have heterogeneous response profiles as a population.
Figure 3: Specificity of the peptide responses of V2r1b-expressing VSNs.
Figure 4: Dose dependency of peptide-induced Ca2+ responses imaged in individual V2r1b-expressing VSNs.
Figure 5: Concentration independence of spatial peptide activation patterns.
Figure 6: Lack of peptide responses in ΔV2r1b-GFP VSNs.
Figure 7: Distribution of anchor residues in human MHC ligands.

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Acknowledgements

We thank M. Konzmann for excellent technical assistance, R. Escher for peptide synthesis, K. Del Punta for a backbone plasmid of the gene targeting vector, W. Tang for blastocyst injections of ES cells and B. Bufe for comments and discussion. This work was supported by the Volkswagen Foundation (T.L.-Z.), Deutsche Forschungsgemeinschaft grants Sonderforschungsbereich 530 (F.Z.) and Schwerpunktprogramm 1392 (F.Z. and P.M.), the Max Planck Society (T.I., P.M. and T.B.), and the US National Institutes of Health (F.Z. and P.M.).

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Author notes

  1. Tomohiro Ishii

    Present address: Present address: Department of Cell Biology, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.,

Authors and Affiliations

  1. Department of Physiology, University of Saarland School of Medicine, Homburg, Germany

    Trese Leinders-Zufall & Frank Zufall

  2. The Rockefeller University, New York, New York, USA

    Tomohiro Ishii & Peter Mombaerts

  3. Max Planck Institute of Biophysics, Frankfurt, Germany

    Tomohiro Ishii & Peter Mombaerts

  4. Max Planck Institute of Immunobiology, Freiburg, Germany

    Thomas Boehm

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  1. Trese Leinders-Zufall
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  3. Peter Mombaerts
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  4. Frank Zufall
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Contributions

T.L.-Z., T.I., P.M., F.Z. and T.B. designed the study. T.L.-Z. and T.I. carried out the experiments. T.L.-Z., T.I., P.M., F.Z. and T.B. analyzed the data. T.L.-Z., T.I., P.M., F.Z. and T.B. contributed reagents and analytic tools. T.L.-Z., P.M., F.Z. and T.B. wrote the paper.

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Correspondence to Frank Zufall or Thomas Boehm.

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Leinders-Zufall, T., Ishii, T., Mombaerts, P. et al. Structural requirements for the activation of vomeronasal sensory neurons by MHC peptides. Nat Neurosci 12, 1551–1558 (2009). https://doi.org/10.1038/nn.2452

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