646 Update TRENDS in Neurosciences Vol.26 No.
12 December 2003
MHC molecules in the vomeronasal organ:
contributors to pheromonal discrimination?
Ashok N. Hegde
Department of Neurobiology and Anatomy, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem,
NC 27157, USA
The vomeronasal organ of the accessory olfactory sys-
tem detects pheromones in several vertebrate species.
Recent studies of vomeronasal sensory neurons have
shown that they express MHC molecules, which in the
immune system help to discriminate self antigens from
non-self antigens. These new findings, along with past
research demonstrating MHC-based olfactory discrimi-
nation, suggest the exciting possibility that MHC mol-
ecules together with vomeronasal G-protein-coupled
receptors play a role in distinguishing related indivi-
duals from unrelated ones based on pheromonal cues.
The nervous system gathers and stores information and
enables organisms to interact with the world. The immune
system defends animals against foreign elements. Recent
publications have begun to show that the nervous system
might use the molecules that were considered to be exclu-
sively in the realm of immunological defense mechanism.
MHC class Ib molecules in vomeronasal sensory neurons
Major histocompatibility complex (MHC) molecules bind
peptide antigens and present them to T lymphocytes
(T cells). T cells mount an immune response only if they
recognize a foreign (non-self) peptide in conjunction with
self MHC. Of the two main classes of MHC, class I
molecules are expressed on the surface of nearly all
nucleated cells, whereas class II molecules are expressed
on antigen-presenting cells of the immune system [1].
Recently, research groups headed by Peter Mombaerts
[2] and Catherine Dulac [3] reported expression of MHC
class Ib genes in the neurons of the vomeronasal organ
(VNO) the chemosensory part of the accessory olfactory
system (AOS). The AOS in several vertebrate species
functions as a parallel olfactory system that mainly detects
pheromones. Pheromones are defined as substances that
are secreted to the outside by an individual and received by
a second individual of the same species, in which they elicit
a specific reaction, for example a particular behavior [4].
In the AOS, vomeronasal sensory neurons (VSNs) sense
pheromones and send signals to the accessory olfactory
bulb (AOB), which is located caudal to the main olfactory
bulb [5]. Often, when an animal senses pheromones it
engages in stereotypical, hard-wired behaviors, such as
aggression or mating. Some pheromone-mediated behav-
iors, however, depend on learning [6].
Corresponding author: Ashok N. Hegde (ahegde@wfubmc.edu).
http://tins.trends.com
The VNO has a crescent-shaped lumen, the concave side
of which has a pseudostratified epithelium consisting of
receptor neurons, basal cells and supporting cells [7]. It
is generally believed that the receptor neurons express
at least one seven-transmembrane G-protein-coupled
receptor from either the V1R family or the V2R family
[8]. V1Rs are coexpressed with Gai2 G-protein subunits
and are restricted to the luminal VN epithelium. V2Rs are
coexpressed with Gao and are restricted to the basal
vomeronasal epithelium [9]. The fibers from the basal
vomeronasal epithelium project to posterior AOB, whereas
the projections from the luminal receptor neurons termi-
nate in the anterior AOB [10] (Figure 1a).
Ishii et al. [2] and Loconto et al. [3] demonstrated the
expression of MHC class Ib genes in the basal layer of the
VNO. These genes are localized to the distal segment of
the MHC locus called H2-M. The genes expressed in the
VNO fall into two families, M1 and M10. The M1 family
has three genes (M1, M9 and M11) and the M10 family
has six genes (M10.1 M10.6). MHC genes and V2Rs are
expressed in specific combinations [2,3]. For example, the
M1 family of genes appears to be exclusively expressed
with a V2R family called V2rf, whereas the M10 family
members are expressed with other V2Rs (Figure 1b).
Loconto et al. [3] showed that vomeronasal neurons
expressing the V2R called EC1 express only M10.5
(which is the same as M10.4 [2]; Figure 1b) out of the
five M10 genes tested. The same group also found that
, 25% of the cells tested expressed more than one M10
gene and one cell expressed three M10 genes (Figure 1b).
Possible functions of MHC molecules in the VSNs
Loconto et al. [3] demonstrated that MHC molecules
are associated with V2Rs and b2-microglobulin. In the
immune system, class I molecules have a polymorphic
a chain and non-covalently-bound b2-microglobulin.
Therefore, it is likely that the MHC molecules in the
VNO have a tertiary structure similar to that of class I
molecules in the immune system (Figure 2). Interestingly,
association with the MHC molecule and with b2-micro-
globulin seems to be essential for expressing the V2Rs on
the dendrites of the vomeronasal receptor neurons [3].
What is the role of MHC molecules in the VNO? Because
MHC molecules function in immune surveillance, they
might have a similar function in the VSNs. Ishii et al. [2]
argue that this is unlikely, given that the VR1-expressing
neurons in the luminal part of the VNO do not express
MHC molecules. Therefore, it is possible that MHC
 Update TRENDS in Neurosciences Vol.26 No.12 December 2003 647

(a)
AOB

Anterior
Posterior

VNO
V NO
MOB

Cortex

s
s s I b m o l e c ule
V1Rs

V2Rs
cla

Luminal
HC
M

Basal

(b)
M9 76100%
M1
5075
2549
1124
M1
0.6

1
M1

1 10

V2rf
M10.6
M10.5
M10.6

M10.5

V2ra
M10.1
M10.5

.5
10
M V2rb
V2rc
EC1-V2R

M
10
.4 .2
10
M

M10.3
TRENDS in Neurosciences

Figure 1. Expression of major histocompatibility complex (MHC) molecules and G-protein-coupled receptors in the vomeronasal epithelium. (a) Organization of the
vomeronasal organ (VNO) and connection of the vomeronasal receptor neurons to the accessory olfactory bulb (AOB), which is located dorsocaudally to the main olfactory
bulb (MOB). Neurons in the luminal part of the vomeronasal epithelium express V1R vomeronasal receptors; those in the basal part express V2Rs and MHC Ib molecules.
The vomeronasal receptor neurons in the luminal layer (purple) connect to the anterior part of the AOB; those in the basal layer (orange) connect to the posterior AOB.
(b) Combinatorial patterns of MHC molecule and V2R coexpression. The MHC Ib molecules expressed in the VNO are shown outside the circle. The blocks in concentric
pattern inside the outer circle represent specific V2Rs, as indicated by color-coding. The length of the block approximately corresponds to the percentage of MHC-Ib-
expressing cells that express a given V2R gene (percentage scale is indicated to the right). The outer circle represents the data from Ishii et al. [2] and the inner circle
shows data from Loconto et al. [3]. The individual or paired names in the inner circle indicate coexpression of MHC Ib genes in vomeronasal receptor neurons that
express the given MHC Ib gene shown outside the outer circle. For example, cells expressing M10.1 can coexpress M10.5 or both M10.5 and M10.6. The inner circle
also shows expression of one V2R (EC1-V2R) in M10.4-expressing cells (9 out of 9 cells) studied by Loconto et al. [3]. The MHC Ib gene nomenclature is from Ishii et al.
[2]; the gene name conversion from Ishii et al. to Loconto et al. is as follows: M10.1 M10.2; M10.2 M10.1; M10.3 M10.3; M10.4 M10.5; M10.5 M10.7;
M10.6 M10.8.

molecules together with a specific V2R function as multi- to the T cells [11]. Two polymorphic domains of the a chain
meric units of pheromone detection. (a1 and a2) in the class I molecules provide a cleft that is
Does the presence of MHC molecules in the VNO have a capable of binding to a large number of peptides and
behavioral significance? A tantalizing possibility is that provide the immune system with broad discriminatory
MHC molecules in the VNO function to discriminate capacity [12]. Arguments against a discriminatory role for
pheromones of related individuals from the pheromones of MHC molecules in the VNO are: (i) MHC Ib molecules are
unrelated individuals. In the immune system, class I MHC not highly polymorphic; (ii) MHC Ib molecules expressed
molecules aid in recognition of foreign antigens by pre- in the VNO lack some of the residues crucial for peptide
senting short, intracellularly processed peptide antigens binding; and (iii) vomeronasal receptor neurons do not
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648 Update TRENDS in Neurosciences Vol.26 No.12 December 2003

Box 1. Possible role of MHC molecules in distinguishing pheromones from related versus unrelated individuals
There are at least two plausible mechanisms for recognition of phero- a weak signal is transmitted to the accessory olfactory bulb (AOB) that
mone identity (i.e. similarity or dissimilarity to self) by complexes of does not produce a behavioral response. If the peptide bound to an
the V2R vomeronasal receptor with major histocompatibility complex MHC Ib molecule is from an unrelated individual, a strong signal is
(MHC) Ib molecules (Figure I). transmitted to the AOB that produces a behavioral response. Weak
signals in the AOB could be enhanced to generate a behavioral response
Differential signaling in vomeronasal sensory neurons or strong signals could be inhibited to suppress a behavioral response.
According to this model (Figure Ia), there has to be at least one peptide Such modification might depend on the substances released onto the
(or protein) component in the pheromone that carries the individual AOB. Reversal of behavioral outcome by modification of the signal in
the AOB can explain preference for individuals with dissimilar MHCs
identity (for example, fragments of MHC molecules). If such a peptide
during mate selection [19] and preference for related individuals during
from a related individual binds to an MHC-Ib-peptide-binding cleft,
nest building [26]. The selection for MHC molecules that weakly bind
peptides similar to self could be analogous to thymic selection of T cells
(a) in the immune system [27]. According to this scheme, the vomeronasal
sensory neurons (VSNs) bearing V2R MHC Ib complexes that respond
(i)
weakly to peptides similar to self are positively selected, perhaps by
elimination of neurons with strongly responding V2R MHC Ib com-
Weak No behavioral
AOB plexes. How can peptides in the pheromone lead to weak or strong
signal response
signal? There is precedence for differential signaling in the immune
system as well as in the nervous system. For example, the same T-cell
Enhancement receptor initiates different responses depending on the peptide bound
MHC Ib of signal [28,29]. In the nervous system, there are numerous reports of G-protein-
coupled receptors (GPCRs) differentially generating signals upon
Behavioral oligomerization with other molecules [30,31]. In the present model,
response when a peptide with low affinity is bound to the MHC Ib molecule, only
Self partial conformational change occurs in the MHC Ib molecule, allowing
V2R a weak interaction with its signal-transducing partner V2R and thus a
weak signal is generated. By contrast, when a peptide binds to the
(ii) MHC Ib molecule with high affinity, the conformational change is
complete, leading to a strong interaction with the V2R (bi-directional
Strong Behavioral arrow in Figure I) and a strong signal is generated. Such ligand-induced
AOB
signal response oligomerization of GPCRs has been reported [32]. Moreover, accessory
proteins called receptor-activity-modifying proteins (RAMPs) can alter
the signaling property of GPCRs [33,34] and MHC Ib molecules have
Supression
MHC Ib of signal been likened to RAMPs [35]. An alternative way of making the signals
from self-related peptides weak would be to increase the strengths of
No behavioral inhibitory synapses in the AOB through an activity-dependent synaptic
response patterning. This could occur during postnatal development when
Non- animals are exposed to familial pheromones.
self The predicted function of MHC molecules in the vomeronasal organ
V2R
differs from the function of MHC molecules in the immune system: MHC
(b) molecules are present on the antigen-presenting cells, and T cells
respond by generating intracellular signals when presented with a
VSNs Glomeruli Mitral cells foreign peptide and self MHC. However, MHC molecules indirectly take
part in the signal transduction in the immune system. For example, the
extracellular domain of CD8, a molecule in the T-cell receptor complex,
contacts class I MHC molecule on its a3 domain. The cytoplasmic tail of
CD8 contacts the Lck tyrosine kinase, which is part of the signal-
transducing machinery in T cells [36]. Therefore, it is conceivable that
MHC Ib molecules can influence signal transduction by V2Rs through
protein protein interaction as described.

OB
Differential
Segregation of MHC Ib-expressing VSN outputs in the AOB
local modulation A second model is that VSN outputs are segregated (Figure Ib). VSN
(e.g. learning) projections connect to several glomeruli, and second order neurons
(mitral cells) connect to glomeruli that receive projections from VSNs
expressing a specific MHC Ib gene (e.g. M10.1 or M10.4) but not to other
glomeruli. In this model, VSNs can recognize peptides similar to self and
peptides dissimilar to self in an equivalent manner. Some MHC Ib
molecules would have higher affinity to peptides similar to self whereas
others would have higher affinity to peptides dissimilar to self. This
M10.1
situation is like that of olfactory receptors, which tend to have a higher
M10.4 affinity for a specific odorant(s). The VSN projections expressing MHC Ib
molecules with higher affinity to peptides similar to self are segregated
TRENDS in Neurosciences from VSN projections with MHC Ib molecules that preferentially bind
peptides dissimilar to self. Recent work has demonstrated projections
from VSNs carrying a given V2R converge at mitral cells in the AOB [37].
Figure I. Plausible mechanisms for recognition of pheromone identity by com-
plexes of V2R vomeronasal receptors with major histocompatibility complex Examination of the work by Ishii et al. [2] and Loconto et al. [3] reveals
(MHC) Ib molecules. (a) Differential signaling in vomeronasal sensory neurons that there are several unique combinations of V2R-MHC Ib that are
(VSNs). (b) Segregation in the accessory olfactory bulb of outputs from VSNs likely to be sufficient to segregate physically the VSN projections. Also,
expressing different MHC Ib genes (e.g. M10.1 and M10.4). Loconto et al. [3] provide evidence for projection of M10.7-carrying

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 Update TRENDS in Neurosciences Vol.26 No.12 December 2003
VSNs to a discrete location in the posterior AOB. The segregated
projections could be differentially modulated by learning or local
release of substances. This model is consistent with pheromonal
memory formation (studied using the pregnancy block paradigm),
which requires mitral cell populations that receive the VSN output to
be at least partially non-overlapping [38]. How might peptides from
related individuals be differentiated from the peptides of unrelated
individuals? It is possible that a reference map for peptides
encountered in early life is generated in the AOB, which serves as
the related to self map. If mitral cells in the AOB that fall outside of
this map are activated by peptides binding to V2R-MHC Ib com-
plexes, those peptides might be recognized as unrelated to self. This
model can explain how mice fostered with parents of dissimilar MHC
types tend to mate with individuals that possess similar MHCs [39,40].
The two models described here are not mutually exclusive. In fact,
a combination of differential signaling in the VSNs and segregation
of projections in the AOB would maximize the capacity of the acces-
sory olfactory system for MHC-based pheromonal discrimination.
express transporter-associated-with-antigen-processing
(TAP)1 and TAP2 molecules, which are essential for
loading the peptide into the peptide-binding cleft of
MHC molecules [3]. However, the limitations in
polymorphism could be compensated by combinatorial
expression of V2Rs and MHC Ib molecules (Figure 1b).
MHC class Ib molecules are known to present antigens
[13]. Also, MHC Ib molecules without all of the
conserved residues can bind peptides [14], and pep-
tide-binding motifs other than those seen in class Ia
molecules are known to play a role in peptide
recognition [15]. TAP1 and TAP2 are necessary for
loading the peptide processed intracellularly. Because
MHC molecules in the VNO would bind extracellular
peptides, TAP1 and TAP2 expression is not necessary.
Therefore, it is possible that the MHC class Ib
Class I MHC V2R
Peptide-binding Ligand-binding
cleft domain
1 2
2 3
microglobulin
TRENDS in Neurosciences
Figure 2. Schematic representation of the structure of a class I major histocom-
patibility complex (MHC) molecule and a typical V2R vomeronasal receptor. Class I
MHC molecules consist of an a chain that is non-covalently attached to b2-micro-
globulin. Both the a chain and b2-microglobulin have disulfide bridges (dashed
lines). The a chain has three extracellular domains (a1 a3) and a transmembrane
domain; domains a1 and a2 constitute the peptide-binding cleft. V2R is a
G-protein-coupled receptor with seven transmembrane domains, a long extra-
cellular domain and intracellular domains. The intracellular domain is likely to be
coupled to a Gao type of G protein, which in turn is likely to be coupled to phos-
pholipase C. In this way, ligand binding to the extracellular domain is believed to
activate transient receptor potential 2 (TRP2)-type ion channels, transmitting the
signal to the accessory olfactory bulb [8]. The putative ligand-binding domain is
based on the model [25] proposed for metabotropic glutamate receptors, to which
V2Rs are similar [8].
http://tins.trends.com
649
molecules expressed on VSNs bind peptides. The
candidate ligands for MHC Ib molecules are the
fragments of class I molecules secreted in the urine
[16] and major urinary proteins [17,18], both of which
have the potential for polymorphism.
The following scenario could be envisaged for the role of
MHC Ib molecules in the VNO, broadly similar to self
non-self discrimination in the immune system. MHC Ib
molecules form a heteromeric complex with V2Rs. When
pheromones are presented to the VNO, a peptide and/or
protein component binds to the MHC Ib molecule and a
different component of the pheromone binds to the V2R.
If the peptide originates from an animal related to the
animal sensing the peptide, a weak signal is transduced
to the AOB and a behavioral response is not generated. If
the peptide bound to the MHC Ib molecule is from an
unrelated animal, then a strong signal is conveyed to the
AOB (Figure Ia of Box 1) and a behavioral response occurs.
Signals might be modified in the AOB by enhancing or
suppressing the signal generated by vomeronasal sensory
neurons, leading to a change in the behavioral output.
Alternatively, the projections from VSNs with different
MHC Ib molecules could be segregated and the relatedness
of the peptide could be determined in the AOB (Figure Ib
of Box 1).
Several studies have indicated that genes in the
MHC locus have a role in imparting olfactory identity
and that animals can distinguish MHC-based differ-
ences in odors and pheromones. For example, mice
prefer to mate with individuals that differ in the MHC
loci [19]. Mice can also be trained to discriminate the
urinary odors of mice differing in MHC haplotypes [20].
Furthermore, even without training, mice can tell
apart pheromones of other mice that differ in their
MHC locus, as Yamazaki et al. [21] demonstrated using
the pregnancy block paradigm. In this paradigm,
females abort the pregnancy if they are exposed to
pheromones of a strange male. Abortion occurred if
females were exposed to pheromones from a male that
differed in only a single MHC locus [21]. Penn and
Potts also showed MHC-based urinary odor discrimi-
nation without training in mice [22]. Isles et al. [23]
demonstrated, using embryo transfer to genetically
unrelated foster mothers, that mice tend to avoid
maternal urinary odors. The preference for MHC
dissimilar mates is also evolutionarily conserved:
humans show preference towards mates with dissim-
ilar human leukocyte antigen haplotypes, as indicated
by marriage patterns [24].
Open questions and future directions
Many questions regarding the role of MHC molecules in
the AOS remain to be answered. How do MHC class Ib
molecules interact with V2Rs and influence signal
transduction by V2Rs? How are specific MHC Ib V2R
combinations generated? How are the signals from MHC-
associated V2Rs processed in the AOB? The work by Ishii
et al. [2] and Loconto et al. [3] has opened a way for exciting
future research towards elucidating the molecular and
neural basis of pheromonal discrimination with the help of
MHC molecules.
650 Update TRENDS in Neurosciences Vol.26 No.12 December 2003
Acknowledgements
Research on the olfactory system in my laboratory is supported by Edward
Mallinckrodt, Jr, Foundation and NARSAD.
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the hands
Sato Honma and Ken-ichi Honma
Department of Physiology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
The circadian clock in mammals is located in the hypo-
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signal transduction are basically unknown. A recent report
by Ikeda et al. provides new insights into the intracellular
signaling pathways involved in conveying circadian clock
information from the core loop to cellular functions. Cyto-
solic Ca21 is proposed to be a key substance linking
the pendulum to the hands of the clock.