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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-07-2348.
CHEMOKINES
From Millennium Pharmaceuticals, Inflammation
Department, Cambridge, MA; the Department of Medicine, Indiana
University School of Medicine, Indianapolis, IN; the Departments of
Microbiology and Immunology, and Pathology and Laboratory Medicine,
Indiana University School of Medicine, Indianapolis, IN; the Department
of Pathology, Harvard Medical School, Boston, MA; and the Joint Program
in Transfusion Medicine, Children's Hospital, Boston, MA.
The chemokine receptors (CCRs) CCR4 and CCR10, and the
cutaneous lymphocyte antigen (CLA), have each been proposed as critical mediators of skin-specific TH lymphocyte homing in mice and
humans. CLA initiates skin homing by mediating
E-selectin-dependent tethering and rolling within cutaneous venules,
but the specific roles of CCR4 and CCR10 are unclear. We have generated
an antihuman CCR10 monoclonal antibody (mAb; 1B5) to illuminate
the individual contributions of these molecules. This mAb allows us to
compare CCR10, CCR4, and CLA expression within human TH
populations. The mAb 1B5 recognizes functional CCR10 expression, as
chemotactic responsiveness to cutaneous T-cell-attracting
chemokine (CTACK)/CCL27 (a CCR10 ligand) parallels the
staining of TH subsets. We find CCR10 expressed by only a
minority (approximately 30%) of blood-borne, skin-homing (CLA+/CCR4+) TH cells. However,
essentially all members of the relatively small "effector"
(CLA+/CCR4+/CD27 Adhesion molecules and tissue-specific homing
Chemokine receptors and tissue-specific homing
Another chemokine receptor, CCR4, is robustly expressed by most skin-homing (CLA+) TH cells in the circulation, but rarely (and at lower levels on the few positives) by intestinal-homing TH cells.15 CCR4 is also expressed at high levels by skin-infiltrating lymphocytes (isolated directly from skin), but not by gut-infiltrating lymphocytes.10 Additionally, the CCR4 ligand TARC/CCL17 is associated with cutaneous (but not intestinal) endothelial cells.15 CCR4 expression can easily distinguish between cutaneous
(CLA+) and intestinal ( The expression of CCR4 by apparently noncutaneous lymphocytes has led to the proposal that CLA and CCR4 must work together to convey skin-specific homing.15 Alternatively, it has been proposed that there may exist another chemokine receptor, with better specificity for cutaneous TH cells than CCR4. In fact, after the associations among CCR4, TARC, and cutaneous TH homing were discovered, another chemokine, cutaneous T-cell-attracting chemokine (CTACK)/CCL27 (originally cloned as ALP in mice20), was found to be expressed by cutaneous keratinocytes.21 CTACK is not a ligand for CCR4, but like TARC, CTACK preferentially attracts CLA+ TH cells from peripheral blood in vitro.21 The receptor for CTACK was identified as CCR10, which has another ligand (MEC, CCL28) expressed within the colon and within secretory tissues, including salivary and mammary glands.22 CCR10 is expressed by a subset of CLA+ TH cells in peripheral blood.23 Thus, CCR4 and CCR10 are both associated with conventionally defined skin homing TH cells from peripheral blood, but the association is imperfect in both cases: CCR4 is present on essentially all skin-homing cells, but also present on other systemic cells. In contrast, CCR10 is absent from non-skin-homing TH cells,23 but only present on a subset of skin-homing TH cells. Peripheral blood TH lymphocytes lacking CD27 and CCR7 In addition to the tissue-specific divisions among TH subsets, there exist other axes of subdivision. For example, a relatively small subset of TH cells does not express the tumor necrosis factor-receptor family member CD2724-26 and/or the chemokine receptor CCR7.24,27 Such cells are found within the CLA+/ 4 7 ,
CLA/47+, and
CLA/47 memory compartments, but not
within the naive (CD45RA+) compartment (virtually all naive
cells express both CD27 and CCR724). The TH
phenotypes that lack these markers have been called
"effector-memory," because they are enriched in recently seen
antigen specificities, and they respond more quickly to antigen than
most other memory TH cells.25-27 Absence of
CCR7 would preclude entry of such cells into lymphoid organs via HEVs
through the known mechanisms,13,14,27 suggesting that such
cells might home through only those nonlymphoid tissues to which they
have become dedicated. Indeed, effector-memory cells are found within uninflamed or inflamed nonlymphoid tissues, often side-by-side with
cells that continue to express both CD27 and CCR7.24 The relationship between effector phenotype and trafficking phenotype has
not yet been thoroughly assessed.
In order to understand the interesting differences between CCR10 and CCR4 expression among human TH subpopulations, we have generated a monoclonal antibody that recognizes functional expression of CCR10 by human lymphocytes. We have performed extensive analyses to compare and contrast CCR10 versus CCR4 expression by TH subsets associated with cutaneous homing. We have examined expression (and functionality) of these receptors by several distinct subsets of peripheral blood TH memory cells, including those classified as "effector" TH cells. Furthermore, we have compared expression of these receptors by TH lymphocytes directly isolated from inflamed cutaneous sites.
Generation of mAbs against CCR10 The murine pre-B lymphoma cell line L1/2 was transfected with an expression vector (pcDNA3.1) containing the human CCR10 DNA sequence, as previously described.28 Transfected pools were chemotaxed to CTACK/CCL27 and/or to MEC/CCL28, and clones with the best chemotactic potential were selected (L1/2 cells expressing human CCRs 1 through 9 were created in the same manner). CCR10-specific monoclonal antibody 1B5 was generated by immunizing C57Bl/6 mice intraperitoneally with 107 CCR10 L1/2 cell transfectants every 2 weeks for 5 to 6 times. The final immunization was performed intravenously 4 days prior to extraction of the spleen for fusion with the SP2/O cell line as described.24 CCR10-specific antibody-secreting hybridoma cell clones were identified by performing immunofluorescence staining of wild-type (WT) and CCR10 L1/2 cells with cell supernatants followed by a fluorescently-labeled antimouse secondary antibody. Fluorescent cells were detected by flow cytometry. Antibody-secreting clones were isolated by multiple rounds of subcloning. For screening the CCR10 mAb against L1/2 cells transfected with other CCRs (Figure 1), each transfectant was stained with a specific mAb to its respective receptor, to ensure high expression levels of the transfected gene (not shown).
Peripheral blood Buffy coats from anonymous healthy donors were obtained from the Children's Hospital (Boston, MA) blood bank. Mononuclear layers were prepared as previously described.12,15,17,24,29,30Skin inflammation Delayed-type hypersensitivity (DTH) responses to Candida extract, and subsequent isolation of lymphocytes from vacuum-blister fluid were performed as described previously.10,24 Experimental human chanchroid was induced by inoculation of healthy, HIV-seronegative volunteers at 3 sites with Haemophilus ducreyi 35000HP (a human passaged isolate of 35000). Sites that evolved into pustules were biopsied 7 to 14 days after inoculation. In some cases, multiple sites from one subject were biopsied and then pooled. Isolation of lymphocytes from biopsied skin using EDTA (ethylenediaminetetraacetic acid) was performed as described previously.10,24 Informed consent was obtained from the subjects in accordance with the guidelines for human experimentation of the US Department of Health and Human Services and the institutional review board of Indiana University-Purdue University at Indianapolis under grants AI31494 and AI27863 to S.M.S. and M01RR00750 to the GCRC at IU. Enrollment procedures, exclusion criteria, preparation of the bacteria, inoculation procedures, and clinical outcomes are described in detail elsewhere.31-33Six-color flow immunocytometry Immunostaining was performed with a 5-step method. Cells were stained first with unconjugated mAb (or its isotype-matched control); followed by polyclonal second-stage Abs; followed by blocking with 3 mg/mL mouse IgG (technical grade; Sigma) and 0.3 mg/mL mouse IgM (technical grade; Sigma); followed by directly-conjugated mAbs; followed by streptavidin conjugate. (1) The first fluorescent color used (color 1) was: CLA-fluorescein isothiocyanate (FITC; HECA-452; BD/Pharmingen, San Diego, CA) or CD27-FITC (M-T271; BD/Pharmingen); (2) color 2: CD27-phycoerythrin (PE; M-T271, BD/Pharmingen) or7-Integrin-PE (FIB-504; BD/Pharmingen); (3) color
3: CD45RA-PE-TR (2H4; Beckman-Coulter, Brea, CA); (4) color 4: IgG2a
isotype control (UPC-10; Sigma), CCR4 (2B10;15 Millennium
Pharmaceuticals), or CCR10 (1B4; Millennium Pharmaceuticals); followed
by goat anti-mouse IgG2a( a)-biotin (Southern Biotechnology,
Birmingham, AL); followed by Streptavidin-PE-Cy7 (Cedarlane
Labs, Ontario, CA); (5) color 5: CCR7 (3D9;24 Millennium
Pharmaceuticals); followed by goat anti-mouse IgM(µ)-Cy5 (Jackson
Immunoresearch, West Grove, PA); and (6) color 6: CD4-allophycocyanin
(APC)-Cy7 (S3.5; Caltag, Burlingame, CA).
Data on stained cells were acquired on dual-laser MoFlo cytometer (Cytomation, Ft. Collins, CO) configured for 6 colors: (1) FITC, (2) PE, (3) PE-TR, (4) PE-Cy7, (5) Cy5, (6) APC-Cy7. Raw data were compensated and analyzed using Summit 3.0 software (Cytomation). Chemotaxis Chemotaxis was performed as described.12,15 For each chemokine for each donor, 2 chemotaxis wells of the following concentrations were set up: 1000 nM, 300 nM, 100 nM, and 30 nM; data are shown in Figure 4 for the optimal concentrations. Recombinant stromal cell-derived factor-1
(SDF-1; PeproTech), recombinant TARC (R&D Systems, Minneapolis, MN) and synthetic CTACK (Gryphon Sciences, South
San Francisco, CA) were used for all experiments shown. Input and
migrated cells were stained with a 5-color protocol: CLA-FITC, CD27-PE
(M-T271, BD-Pharmingen), CD45RA-PETR, CD4-biotin (13B8.2,
Beckman-Coulter) + streptavidin-PE-Cy7, and CCR7 (7H12, Millennium
Pharmaceuticals) + goat anti-mouse IgG (H&L)-Cy5
(Jackson Immunoresearch).
Generation of a mAb to human CCR10 A monoclonal antibody against human CCR10 was developed by immunizing mice with L1/2 cells (a murine pre-B lymphoma) transfected with human CCR10 mRNA in a mammalian expression vector.24 The resulting mAb, 1B5, recognized CCR10-transfected (but not WT) L1/2 cells (Figure 1). 1B5 did not recognize L1/2 cells transfected with any of the other known CC chemokine receptors (CCR1 through 9 plus CCR11/GusB) (Figure 1).Expression of CCR10 by peripheral blood TH cells We first examined the CCR10 expression of naive TH and the 3 peripheral blood memory TH subsets classically defined by the homing receptors CLA or47-integrin34,35 (Figure
2A). Among the memory TH populations, CCR10 expression was
restricted to the CLA+/47 "skin
homing" subpopulation (Figure 2B). Interestingly, however, CCR10 was
not expressed by approximately 70% of the CLA+
TH population. CCR10 was absent from naive TH
cells (Figure 2B).
Two-color plots of CCR10 or CCR4 versus CLA are shown for the memory
TH-gated population in Figure 2C. CCR4 stains the vast majority of CLA+ TH cells with equal intensity
and also stains a subset of CLA Characterization of the CLAhi-enriched memory TH subset that expresses CCR10, and comparison with CCR4 expression Another previously identified axis of subdivision within the peripheral blood CLA+ TH memory compartment (as well as the other TH memory compartments) involves CD27 and CCR7 expression.24-27 We therefore asked whether the observed patterns of CCR10 expression correlate with CD27 and/or CCR7 expression by using 6-color flow cytometry.The upper panel in Figure
3A shows that peripheral blood CLA+ TH cells are
spread among all 4 quadrants of a CD27 versus CCR7 plot. However, plots
of CLA versus CD27 or CCR7 distinguish the individual subsets more
clearly (Figure 3A, lower plots). The latter type of plot was used to
enumerate CLA+ subsets displaying the 4 permutations of
CD27 and CCR7 expression for 10 healthy donors (Figure 3B).
Interestingly, the CD27
For simplicity, we have chosen to focus on the 2 most extreme
phenotypes identified here for more detailed analysis: the
CD27 Responsiveness of peripheral blood TH subsets to the CCR10 ligand CTACK Whenever possible, it is important to confirm chemokine receptor flow cytometry results through an independent method. We therefore set out to determine whether CCR10 expression patterns (determined by 1B5) correlate with functional responses to CTACK/CCL27 (a CCR10 ligand) in standard chemotaxis assays. Each of the populations examined express very similar amounts of the SDF-1 receptor CXCR4 (J.J.C., unpublished data, November 2000). This fact allows normalization of their CTACK-mediated migration to that of SDF-1, to correct for potential intrinsic differences in migration rates among the various populations (Figure 4, upper scale). Migration is also plotted (on the same graphs) as percent of input (Figure 4, lower scale) with comparable outcome. Figure 4 clearly demonstrates that the double-negative CLA+ TH population responds significantly better to CTACK than any of the other populations tested (including the double-positive CLA+ TH population, Figure 4, left panel). There was no significant difference in TARC responsiveness between double-positive and double-negative populations (Figure 4, right panel).
CCR10 expression by tissue-infiltrating lymphocytes from inflamed skin The data indicate that while CCR4 is expressed by most CLA+ TH cells in blood, CCR10 is expressed only by a minority subset. We therefore asked whether the CCR10+ subset might have an advantage over other CLA+/CCR4+ TH cells in its ability to home to inflamed cutaneous sites.We chose to analyze the homing phenotypes of TH cells directly isolated from 2 different types of cutaneous lesions. The first was a widely studied DTH model, in which cutaneous inflammation is induced by intradermal injection of a sterile extract of Candida albicans.10 The second was an experimental cutaneous bacterial infection of human volunteers with H ducreyi. H ducreyi causes chancroid, a sexually transmitted genital ulcer disease that facilitates efficiency of HIV transmission by disruption of epithelial barriers and infiltration of TH (CD4+) cells into the lesions.36 Essentially all of the TH cells isolated from DTH skin were
of the CD45RAlo/neg memory phenotype (Figure
5A). TH cells from donor-matched peripheral blood contained
40% to 50% CD45RAhi naive cells (not shown), suggesting
that the skin-derived samples were not significantly contaminated with
peripheral blood lymphocytes. The number of cells expressing CLA was
greatly enriched with respect to peripheral blood memory TH
cells, but the ratio of CD27/CCR7 double positives to double negatives
did not significantly differ from that of peripheral blood memory
CLA+ TH cells (Figure 5B-C). CCR4 was
expressed by skin-infiltrating TH cells at greatly enriched
levels, but, interestingly, CCR10 was not (Figure 5D-E).
The identical flow cytometry was performed on a total of 3 DTH and 3 H ducreyi lesions, and the data presented as bar graphs (Figure
6). For both types of lesion, the ratio of memory to naive cells was
significantly different from that of the peripheral blood
TH population from matched donors (not shown). The
proportion of CLA+ and CCR4+ TH
cells was significantly increased with respect to the peripheral blood
memory population. In contrast, the ratio of CD27/CCR7 double positives
to double negatives was not significantly different from that of
peripheral blood memory TH cells. Most importantly for the
present study, the proportion of CCR10+ cells was not
significantly enriched with respect to peripheral blood
CLA+ memory TH cells.
We have performed a detailed analysis of functional CCR4 and CCR10 expression by peripheral blood- and skin-derived human TH cells. These studies are part of an ongoing effort to understand the role of chemokines and their receptors in cutaneous (and other tissue-specific) lymphocyte homing. Peripheral blood contains a heterogeneous mixture of TH (and other) lymphocytes, many with distinct trafficking patterns.34,35 Therefore, within a given tissue, the specific enrichment of cells bearing a particular homing molecule suggests the molecule's potential importance in homing to that tissue. We confirm that lymphocytes expressing CLA and CCR4 are greatly
enriched within the cutaneous lesions studied here, which is not the
case for other tissues.10,15 CCR10 is slightly enriched in
skin when compared with the total circulating memory TH
pool. However, CCR10 is not enriched in cutaneous sites when compared with CLA+ memory T cells from peripheral blood. Thus
CLA+/CCR4+ TH cells that express
CCR10 have no apparent advantage over their CCR10 One should consider the caveat that cell-surface CCR10 might indeed be necessary for skin infiltration, but becomes down-regulated upon entry. This is clearly not the case for CCR4, which is expressed at comparable levels by both CLA+ blood TH cells and skin-infiltrating TH cells.10 Further, we demonstrated that CCR10 expression is greatly enriched on cells lacking CD27 and/or CCR7 in peripheral blood (Figure 3C-D), and that the CD27/CCR7 phenotype of cutaneous-infiltrating cells is not significantly different from that of peripheral blood CLA+ memory TH cells. Therefore, as the CD27/CCR7-negatives are not enriched in cutaneous sites, there is no reason to propose that CCR10 expression has been underrepresented by this assay. Why are there 2 "cutaneous" chemokine receptors? Both CCR10 and CCR4 have qualities that suggest a role in TH homing to cutaneous sites. However, our data suggest that, unlike CCR4, CCR10 is not a necessary component of cutaneous homing for most TH cells. Within the skin-homing TH population, CCR10 is associated with the "effector" phenotype. Virtually all those cells displaying the most extreme effector phenotype (ie, CD27/CCR7 double negatives) express CCR10.In vitro studies make it clear that effector TH cells are functionally distinct from conventional memory TH cells.25-27 However, it is not clear how such cells actually contribute to in vivo immune responses. It is possible that such effector TH cells play a regulatory role in coordinating immune responses for the tissues through which they traffic. For example, CLA+ cutaneous "effector" TH cells may coordinate the responses of conventional cutaneous CLA+ memory TH cells, either positively or negatively. Part of this role may involve coordinating the traffic of conventional TH cells through the skin, perhaps by regulation of TARC/CCR4 interactions. If this scenario is proved true, effector TH cells would require a TARC/CCR4-independent mechanism for skin entry. CTACK/CCR10 interactions could provide such a mechanism. This hypothesis would predict that cells entering the skin in the absence of TARC/CCR4 interactions (ie, in CCR4-deficient mice, as discussed in "Murine models"37) would be greatly enriched in effector TH cells. The potential effect that blocking CTACK/CCR10 interactions would have on cutaneous inflammation is less straightforward to predict. If effector cells tend to positively regulate the intensity of skin inflammation, such blocking might be expected to dampen the response. If, in contrast, effector cells tend to negatively regulate inflammation, blocking of CCR10 might actually exacerbate skin inflammation. CCR10 and other types of skin inflammation Recent immunohistochemistry studies suggest that CCR10 is expressed by many cells within allergic dermatitis and psoriatic lesions.23 However, it is not clear (from this type of data) what proportion of TH cells express CCR10 within these lesions. Therefore, it is not clear that these findings differ significantly from our own. However, if CCR10 is indeed expressed by many TH cells in such lesions (as suggested by Homey et al23), then CCR10 may play a more pervasive role in homing to allergic dermatitis and psoriatic sites than played in the DTH and bacterial skin lesions studied here. In such a case, one would expect the allergic dermatitis and psoriatic sites to have more CD27/CCR7 double-negative cells than DTH and bacterial skin lesions.Murine models Two recent murine studies of dinitrofluorobenzene (DNFB)-induced DTH responses have demonstrated an inhibitory effect of anti-CTACK polyclonal antibodies on cutaneous lymphocyte homing. In the first model (on the C57Bl/6 background37), treatment with anti-CTACK inhibited cutaneous lymphocyte homing in CCR4-deficient but not WT mice. This implies that signaling through both CCR4 and CCR10 must be blocked to influence cutaneous homing through the chemokine system. In the second model (on the Balb/c background23), treatment with very large amounts of anti-CTACK polyclonal Ab alone influenced cutaneous TH homing in WT mice. Such classical murine DNFB-induced models of atopic dermatitis, however, raise concerns when used to study cutaneous TH homing in this particular case: although large numbers of TH cells do indeed enter such lesions, skin swelling itself (as measured by changes in ear thickness after application of DNFB) is not T-cell-dependent. (We have demonstrated that the classical DNFB-induced ear thickness procedure [used in both of the murine studies under discussion] produces swelling in all T-cell-deficient mouse strains tested, including homozygous nude, scid, and Rag-1- or Rag-2-deficient strains. In such experiments, the increases in ear thickness were indistinguishable from those induced in WT mice of the same genetic background [J.J.C., unpublished data, June 2002]). Thus, antibodies to CTACK must have a not-yet-understood influence on some component of the intrinsic immune system to explain their effects on T-cell-independent swelling.Therefore, the observed influence of anti-CTACK on cutaneous lymphocyte homing should not necessarily be interpreted as having a direct effect on T-cell trafficking. It is equally plausible that the observed reduction of T-cell infiltrates within DNFB-treated skin is secondary to anti-CTACK-mediated prevention of the inflammatory response itself, through effects on the intrinsic immune system. Further studies will be required to resolve this issue, such as reproducing the finding in strictly T-cell-dependent models of cutaneous inflammation. Although this manuscript addresses only the putative skin-homing TH aspects of CCR10/CTACK interactions, it should be noted that another CCR10 ligand (MEC/CCL28) is expressed by exocrine tissues.22 This suggests that CCR10 may have other roles in leukocyte trafficking yet to be discovered. Conclusions Our data support the notion that CLA and CCR4 are intimately associated with the process by which most memory TH cells specifically enter the skin. We suggest that CCR10 may be part of an alternative cutaneous homing pathway utilized primarily by the less numerous "effector" subset of the TH lymphocyte pool.
We thank Nasim Kassam and Meghan Wells from Millennium Pharmaceuticals for invaluable technical assistance. We thank Drs L. Silberstein, L. Jopling, M. Wurbel, and E. Baekkevold for critical reading of the manuscript and useful discussions of the data. We also thank Rob Hromas for instigating the Spinola Lab/Campbell Lab collaboration.
Submitted August 1, 2002; accepted October 10, 2002.
Prepublished online as Blood First Edition Paper, October 24, 2002; DOI 10.1182/blood-2002-07-2348.
Supported by National Institute of Allergy and Infectious Diseases (NIAID) grants AI46784 (J.J.C.), and AI31494 and AI27863 (S.M.S.), and M01RR00750 to the General Clinical Research Center (GCRC) at Indiana University (IU). T.L.H. was supported by T32AI07367 from NIAID.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: James J. Campbell, Children's Hospital, Bader 401, 300 Longwood Ave, Boston, MA 02115; e-mail: james.campbell{at}tch.harvard.edu.
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Abstract
Introduction
subset of peripheral blood memory CD4+ lymphocytes contains functionally differentiated T lymphocytes that develop by persistent antigenic stimulation in vivo.
Eur J Immunol.
1992;22:993-999