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Vol. 54, Issue 2, 227-229, June 2002
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
Abstract
I. Introduction
A. CXCR6
B. CCR11
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An update of the International Union of Pharmacology nomenclature for chemokines is outlined, defining one new receptor type, CXCR6, and disqualifying the putative receptor, CCR11.
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I. Introduction |
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In the year 2000, the International Union of Pharmacology
Committee on Receptor Nomenclature and Drug Classification
(NC-IUPHAR2)
approved a nomenclature system for chemokine receptors, the major seven
transmembrane (7TM) receptors of the immune system, as recommended by
the NC-IUPHAR Chemokine Receptor Subcommittee (Murphy et al., 2000
). At
that time, the chemokine receptor family consisted of 18 7TM proteins
in humans, which were divided into four subfamilies based on chemokine
subclass specificity. Two additional molecules, named Duffy and D6,
which both have 7TM structure and bind chemokines but lack a known
signaling function, were excluded from the nomenclature system, as were
a group of functional 7TM chemokine receptors encoded by herpesviruses
(Rosenkilde et al., 2001). The nomenclature system is logical,
noncontroversial, and universally accepted and used (Table
1). Moreover, it has served as a template
for the creation of a chemokine ligand nomenclature system (Zlotnik and
Yoshie, 2000). Both systems have facilitated communication among
immunologists and pharmacologists as these molecules have become
important drug targets in immunologically mediated disease and
HIV/acquired immunodeficiency syndrome. Since publication of the
NC-IUPHAR document reporting the nomenclature system in the year 2000, one new receptor subtype, CXCR6, has been identified (Matloubian et
al., 2000; Wilbanks et al., 2001), and one other subtype, CCR11, has
been disqualified (Schweickart et al., 2000, 2001). Duffy and D6 remain
as binding sites. The aim of the present article is to provide a brief
update on these receptors.
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A. CXCR6
CXCR6 was originally cloned as an orphan receptor in 1997 by three
independent groups who assigned three different names to it: STRL33
(seven transmembrane receptor-like from clone 33), BONZO, and TYMSTR (T
lymphocyte-expressed seven-transmembrane domain receptor) (Alkhatib et
al., 1997; Deng et al., 1997; Liao et al., 1997; Loetscher et al.,
1997). It was considered most likely to be a chemokine receptor because
1) the gene was located on human chromosome 3p21 within the major
chemokine receptor cluster, 2) the sequence was most highly related to
chemokine receptors, 3) the RNA was expressed in activated T
lymphocytes, and 4) like many other chemokine receptors, it could
function as a cell entry factor for HIV. A particularly interesting
feature is its ability to support cell entry by simian immunodeficiency
virus and both X4 and R5 strains of HIV.
Although many chemokine receptors have multiple shared ligands, CXCR6
binds a distinct ligand, designated CXCL16 (Matloubian et al., 2000;
Wilbanks et al., 2001). CXCL16 has a unique hybrid structure, with
features heretofore found separately in two other chemokine subclasses.
In particular, it has the CXC motif, which defines members of the CXC
subclass of chemokines, and a multimodular structure consisting of a
transmembrane region and a chemokine domain suspended by a mucin-like
stalk previously found only for the CX3C chemokine CX3CL1. The CXCL16
chemokine domain also has characteristics of the CC chemokine subclass.
CXCL16 is expressed on the surface of antigen-presenting cells (B
cells, macrophages, dendritic cells in lymphoid organ T cell zones) and
by cells in the splenic red pulp (Matloubian et al., 2000). Functional
CXCL16 is also shed from macrophages (Wilbanks et al., 2001). CXCR6 is expressed preferentially on memory T cells and on activated Th1 and Tc1
effector T cell subsets (Unutmaz et al., 2000; Kim et al., 2001). The
exact biological role of CXCL16/CXCR6 is unknown, but reasonable
hypotheses for this role include attraction of activated T lymphocyte
subsets during inflammation, facilitation of immune responses via
cell-cell contact, and guidance of T cell trafficking in the splenic
red pulp. CXCL16 is also expressed in the thymic medulla and in some
nonlymphoid tissues, suggesting roles in thymocyte development.
B. CCR11
The human homolog of the bovine orphan gustatory receptor PPR1 was
originally designated CCR11 based on a report by Schweickart et al.
(2000) indicating that, when expressed in a transformed mouse B cell
line, it functioned as a chemotactic receptor for the monocyte
chemoattractant protein family of chemokines (CCL2, CCL8 and
CCL13). However, an independent report, published in the same month,
found that this same molecule (which was designated by a different
name, CCR10) did not bind these chemokines, but instead bound CCL19,
CCL21 and CCL25 with high affinity (Gosling et al., 2000).
Nevertheless, no signaling function could be identified. On review, the
first group confirmed that CCR11 bound CCL19, CCL21 and CCL25 in two
independent cell lines and found that the original transfected cell
line used in their study expressed RNA for endogenous mouse CCR2, a
known receptor for CCL2, CCL8, and CCL13, but lacked detectable RNA for
exogenous CCR11 (Schweickart et al., 2001). They concluded that the
original data were not due to CCR11 but instead may be attributable to
up-regulation of endogenous murine CCR2 gene. Since there is now no
signaling response ascribed to the receptor, this molecule does not
qualify for a CCR# designation and the terms CCR10 or CCR11 should no
longer be used to describe it. Moreover, at approximately the same time
in 2000, two groups independently identified the receptor for CCL27,
which they named CCR10 (Homey et al., 2000; Jarmin et al., 2000). Since
this molecule mediates chemotactic signaling, it is a bona fide
chemokine receptor and qualifies for this designation.
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Footnotes |
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1 Chairman of the Subcommittee on Chemokine Receptors, International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification.
Address correspondence to: Dr. Philip M. Murphy, Laboratory of Host Defenses, Bldg. 10, Room 11N113, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892. E-mail: pmm{at}nih.gov
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Abbreviations |
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NC-IUPHAR, International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification; 7TM, seven transmembrane; HIV, human immunodeficiency virus.
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0031-6997/02/5402-227-229$7.00
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