Cluster Of Differentiation Antigens Research Articles

Immunophenotyping in leukemia and its diagnostic significance

The identification of cell surface markers, defined as clusters of differentiation antigens (CD’s) could be used to classify and sub-classify leukemia. Although the same antigens are expressed on normal cells, the phenotype on malignant cells are aberrantly and frequently asynchronously expressed and may be present in combinations not observed in normal blood or bone marrow. Aberrant expression of surface antigens corresponds with poor therapeutic response and short survival. Additional surface marker analysis complementary to morphologic evaluation and cytochemical staining has greatly improved our ability to characterize hematologic malignancies. A review and illustration on the diagnostic significance of immunophenotyping in leukemia will be presented. Data from 225 patients having complete assessments including morphology, cytochemistry and immunophenotyping in the period of 1994-2001 were collected and analyzed. Based on morphologic evaluation and cytochemistry, the diagnosis of acute myeloid leukemia and acute lymphoblastic leukemia were established in 51.1% and 48.9% of cases, respectively. Based on immunophenotyping AML was found in 49.0% of the cases. ALL could be classified into 4.9% pre-B-ALL, 18.7% B-ALL, and 14.7% T-ALL. Cases expressing cross-lineage antigens were found in 12.7%. The prognostic significance of these aberrant expression of antigens for those cases has yet to be established but some of the cases responded poorly to therapy. Immunophenotyping provides the tool to: 1) distinguish normal from clonal populations of leukemic cells; 2) define lineage and reveal the stage of maturation; 3) identify inappropriate expression of lineage associated antigens; 4) provides more informations to establish diagnosis and prognosis compared to standard methods. (Med J Indones 2004; 13: 195-202) Keywords: Immunophenotyping, clusters of differentiation antigens, lineage associated antigens

Increases in leukocyte cluster of differentiation antigen expression during cardiopulmonary bypass in patients undergoing heart transplantation.

Cardiopulmonary bypass (CPB) is essential in heart transplantation surgery. It is also used in coronary artery grafting surgery where it has been associated with a postoperative inflammatory response. This manifests as an increase in pro-inflammatory proteins like interleukin-8 and tumour necrosis factor alpha accompanied by increases in neutrophil populations and increased expression of cluster of differentiation (CD) antigens. The latter have been investigated using flow cytometry, which is limited to the measurement of three to four CD antigens simultaneously. We have developed a novel antibody array that can simultaneously measure the expression of 72 different CD antigens. The purpose of this study was to use this technology to measure CD antigen expression in patients undergoing CPB during heart transplantation. Twelve patients undergoing this operation were studied. A preoperative sample acted as an internal control while a second sample taken during CPB was the comparator. No previous studies have examined changes in CD antigen expression during heart transplantation. We report an increase in the expression of 10 different CD antigens across all patients between the two time points.

Identification of repertoires of surface antigens on leukemias using an antibody microarray.

We have previously described a microarray of cluster of differentiation (CD) antibodies that enables concurrent determination of more than 60 CD antigens on leukocytes. This procedure does not require protein purification or labeling, or a secondary detection system. Whole cells are captured by a microarray of 10 nL antibody dots immobilized on a nitrocellulose film on a microscope slide. Distinct patterns of cell binding are observed for different leukemias or lymphomas. These haematological malignancies arise from precursor cells of T- or B-lymphocytic, or myeloid lineages of hematopoiesis. The dot patterns obtained from patients are distinct from those of peripheral blood leukocytes from normal subjects. This microarray technology has recently undergone a number of refinements. The microarray now contains more CD antibodies, and a scanner for imaging dot patterns and software for data analysis provide an extensive immunophenotype sufficient for diagnosis of common leukemias. The technology is being evaluated for diagnosis of leukemias with parallel use of conventional diagnostic criteria.

Monoclonal antibodies to mouse cell-surface antigens.

The cluster of differentiation (CD) nomenclature, originally devised by the International Workshop on Human Leukocyte Differentiation Antigens (HLDA) to classify leukocyte surface antigens, has become more accepted by researchers in nonhuman animal models. The CD homologues from other species are usually identified by multiple studies, including biochemical, functional analysis, cloning, and immunological assays. This unit compiles a complete (as of August, 2001) list of monoclonal antibodies (mAb) to the mouse CD antigens and several non-CD surface antigens that are commonly used as phenotypic and functional markers in the mouse system. There are many reagents recognizing polymorphic epitopes of the mouse MHC and different subunits of TCR; for simplicity, only a few mAbs to the framework determinants of these molecules are listed here.

Negative factor from SIV binds to the catalytic subunit of the V-ATPase to internalize CD4 and to increase viral infectivity.

The accessory protein negative factor (Nef) from human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) is required for optimal viral infectivity and the progression to acquired immunodeficiency syndrome (AIDS). Nef interacts with the endocytic machinery, resulting in the down-regulation of cluster of differentiation antigen 4 (CD4) and major histocompatibility complex class I (MHCI) molecules on the surface of infected cells. Mutations in the C-terminal flexible loop of Nef result in a lower rate of internalization by this viral protein. However, no loop-dependent binding of Nef to adaptor protein-2 (AP-2), which is the adaptor protein complex that is required for the internalization of proteins from the plasma membrane, could be demonstrated. In this study we investigated the relevance of different motifs in Nef from SIV(mac239) for its internalization, CD4 down-regulation, binding to components of the trafficking machinery, and viral infectivity. Our data suggest that the binding of Nef to the catalytic subunit H of the vacuolar membrane ATPase (V-ATPase) facilitates its internalization. This binding depends on the integrity of the whole flexible loop. Subsequent studies on Nef mutant viruses revealed that the flexible loop is essential for optimal viral infectivity. Therefore, our data demonstrate how Nef contacts the endocytic machinery in the absence of its direct binding to AP-2 and suggest an important role for subunit H of the V-ATPase in viral infectivity.

Local cluster of differentiation antigen (CD) in VIN

Local cluster of differentiation antigen (CD) in VIN

Cluster of differentiation antigen 4 (CD4) endocytosis and adaptor complex binding require activation of the CD4 endocytosis signal by serine phosphorylation.

Cluster of differentiation antigen 4 (CD4), the T lymphocyte antigen receptor component and human immunodeficiency virus coreceptor, is down-modulated when cells are activated by antigen or phorbol esters. During down-modulation CD4 dissociates from p56(lck), undergoes endocytosis through clathrin-coated pits, and is then sorted in early endosomes to late endocytic organelles where it is degraded. Previous studies have suggested that phosphorylation and a dileucine sequence are required for down-modulation. Using transfected HeLa cells, in which CD4 endocytosis can be studied in the absence of p56(lck), we show that the dileucine sequence in the cytoplasmic domain is essential for clathrin-mediated CD4 endocytosis. However, this sequence is only functional as an endocytosis signal when neighboring serine residues are phosphorylated. Phosphoserine is required for rapid endocytosis because CD4 molecules in which the cytoplasmic domain serine residues are substituted with glutamic acid residues are not internalized efficiently. Using surface plasmon resonance, we show that CD4 peptides containing the dileucine sequence bind weakly to clathrin adaptor protein complexes 2 and 1. The affinity of this interaction is increased 350- to 700-fold when the peptides also contain phosphoserine residues.

Expression of interleukin-2 receptor, CD25, on CD4 lymphocytes in response to varicella-zoster virus antigen among patients with malignancies immunized with live attenuated varicella vaccine.

Varicella in an immunocompromised host is often serious or life threatening. A live attenuated varicella vaccine was developed in Japan. It has been reported that the varicella vaccine is safe and highly protective against severe varicella in children with leukemia and other malignancies. It is important to investigate the persistence of varicella-zoster virus (VZV)-specific cell-mediated immunity in patients with malignancies who have been immunized with varicella vaccine. Sixteen patients with malignancies and 11 controls had been immunized with attenuated live varicella vaccine. The duration from vaccination to the study ranged from 2 to 16 years (mean 10 years). Nineteen patients and 20 controls had experienced natural varicella infection. Peripheral blood mononuclear cells (PBMC) from patients and controls were cultured with VZV antigen for 6 days and the percentage of cluster of differentiation antigen (CD)25 among CD4 lymphocytes was calculated by flow cytometry. The percentage of CD25-positive cells among CD4 lymphocytes significantly increased in response to the VZV antigen in vaccinated patients and patients with past natural varicella infection as observed in the controls. These data show that VZV-specific cell-mediated immunity is induced and persists in patients with malignancies after immunization with live varicella vaccine.

Reduced integrin alpha3 expression as a factor of poor prognosis of patients with adenocarcinoma of the lung.

We investigated the possible association between integrin alpha3 and motility-related protein (MRP-1), cluster of differentiation antigen 9 (CD9) gene expression in non-small-cell lung cancer (NSCLC) and evaluated the prognostic significance of integrin alpha3 expression. We performed a retrospective study of integrin alpha3 and MRP-1/CD9 expression in resected tumor tissues from 151 NSCLC patients using quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. The ratio of integrin alpha3/beta-actin expression ranged from 0 to 5.87 (mean was 0.80; median, 0.70). Using the cutoff value of 0.7, there were 78 (52%) integrin alpha3-positive tumors and 73 (48%) tumors with reduced integrin alpha3 expression. The immunohistochemical results agreed well with those of the RT-PCR assays, and 88% had no discrepancy. In case of discrepancy, the results of RT-PCR were used in specimen classification. Integrin alpha3 gene expression was independent from MRP-1/CD9 gene expression. No significant association was found between integrin alpha3 expression and the patients' clinical characteristics. The overall survival rate of patients with integrin alpha3-positive NSCLCs was only slightly better than that of individuals whose tumors had reduced integrin alpha3 expression (55.9% v 47.1%; P = .085). By comparison, the overall survival rate of patients with integrin alpha3-positive adenocarcinomas was strikingly greater than in those whose tumors had reduced gene expression (54.4% v 35.2%; P = .004). Multivariate analysis with the Cox regression model of NSCLC and adenocarcinoma indicated that integrin alpha3 expression correlated better (P = .0188 and P = .0008, respectively) with the overall survival rate than other variables, except lymph node status. No significant association was found between integrin alpha3 and MRP-1/CD9 gene expression in lung cancer. However, reduced integrin alpha3 expression is a poor prognosis factor in patients with adenocarcinomas.

Overview of the Second International Workshop to define swine cluster of differentiation (CD) antigens

The aim of the Second International Swine Cluster of Differentiation (CD) Workshop, supported by the Veterinary Immunology Committee (VIC) of the International Union of Immunological Societies (IUIS), was to standardize the assignment of monoclonal antibodies (mAb) reactive with porcine leukocyte differentiation antigens and to define new antibody clusters. At the summary meeting of the workshop in July, 1995, revisions in the existing nomenclature for Swine CD were approved, so that the rules are now in accord with those for human and ruminant CD. Swine CD numbers will now be given to clusters of mAb to swine orthologues of human CD molecules when homology is proven by (1) suitable tissue distribution and lymphoid cell subset expression, (2) appropriate molecular mass of the antigen recognized by the mAbs, and (3) reactivity of mAbs with the cloned swine gene products, or cross-reactivity of the mAb on the human gene products. In some cases, this reactivity would not be fully proven, mainly due to the lack of cloned gene products; for these CD antigens, the respective clusters will be assigned by the prefix `w' which will lead to `wCD' antigens. As a result of the Second International Swine CD Workshop the assignment of 16 mAb to existing CD groups (CD2a, CD4a, CD5a, wCD6, wCD8, CD14, CD18a, wCD21, wCD25) was confirmed, and 2 mAb to existing swine workshop clusters (SWC). More importantly, for the work on the porcine immune system, was the definition of 5 new swine CD antigens, namely CD3 (recognized by 6 new mAb and 3 epitopes), CD16 (1 new mAb), wCD29 (2 mAb), CD45RA (3 mAb) and CD45RC (1 new mAb). Finally, the demarcation of two new SWC molecules in swine, SWC8 (2 mAb) and SWC9 (2 mAb) was confirmed.

Structure of CD26 (dipeptidyl peptidase IV) and function in human T cell activation.

1996 was the 10th anniversary of the establishment of the cluster of differentiation antigen, CD26 by the Second Workshop and Conference on Human Leukocyte Differentiation Antigens1. First described as a T cell activation antigen, CD26 was found to he strongly expressed on subsets of both activated CD4 and CD8 T cells2. Subsequent work showed the expression of CD26 on activated Nk cells, B cells and B cell lines and demonstrated CD26 expression on a variety of different cell types, most abundantly on epithelia of the intestine, prostate and the proximal tubuli of the kidneys3,4,5. Furthermore, it was demonstrated that CD26 possesses enzymatic activity, dipeptidyl peptidase IV (DPP IV; EC 3.4.14.5), in its extracellular domain4 and is identical to the previously described adenosine deaminase (ADA, EC 3.5.4.4) binding protein6,7. Recent studies indicate that CD26 plays a seminal role in T cell costimulation and may be involved in severe combined immunodeficiency and HIV infection 8,9.

Quantitative analysis of leukocyte membrane antigen expression: normal adult values.

In this paper the normal ranges of the expression of various differentiation antigens, referred to by their cluster of differentiation (CD) numbers, are described on the lymphoid, monocytic, and polymorphonuclear (PMN) blood populations in normal healthy individuals. The values expressed as antibody binding capacity per cell (ABC/cell) are related to the density of antigenic molecules expressed by these cells. These values have been quantitated by the quantitative indirect immunofluorescence (QIFI) test which renders the ABC/ cell values for the different antigens directly comparable and defines a "league table," i.e., an enumeration of antigen expression on the three main cell types studied. The values for occasional antigen that are expressed differently in adults and the elderly or men and women (CD5, CD8, and CD18) are also shown. Furthermore, the QIFI test is used in two-color immunofluorescence for defining the subset heterogeneity within the T lineage for the CD2 and CD7 antigen within the separately analyzed CD45RA and CD45RO subsets. These quantitative immune phenotype analyses, also referred to as quantimetry, show variations in ABC values if different monoclonal antibodies (MAbs) are used, although these differences are frequently minor. Therefore, using whole blood and well-characterized MAbs, we established values of antigen density in normal adults which can be regarded as control values for the various pathological conditions where CD antigen expression may be altered.

Nasal mucosal cells in human immunodeficiency virus type 1-seropositive patients with sinusitis.

Recently, sinusitis has been recognized as a frequent clinical problem in human immunodeficiency virus (HIV-1)-infected individuals. We hypothesized that quantitative defects in immune cells in the nasal mucosa of HIV-positive subjects might mirror those in the peripheral blood and explain a predisposition to sinus disease in this population. Nasal mucosa biopsies were obtained from three different groups of patients-HIV-1 seropositive with sinusitis, HIV-1 seronegative with sinusitis, and HIV-1 seronegative without sinusitis (normal volunteer)-and phenotyped for cluster of differentiation antigen (CD) markers. In this study, we found patients with HIV-1 and sinus disease to have significantly lower numbers of both CD3 and CD4 nasal mucosa lymphocytes than seronegative controls in the nasal mucosa (P < 0.05, P < 0.01, respectively). A correlation between nasal mucosal CD4 cells and peripheral-blood CD4 cells was noted (R = 0.67, P < or = 0.01). No deficiency in the number of nasal mucosa T or TC type mast cells was noted for the HIV-1-positive sinusitis group. Further study is warranted to define more completely the pathophysiology and microbiology of, and therapy for, this important clinical problem.

Lipopolysaccharide modulation of a CD14-like molecule on porcine alveolar macrophages.

Cluster of differentiation antigen 14 (CD14) functions as a receptor for lipopolysaccharide (LPS) LPS-binding protein (LBP) complexes. Because LPS has varying effects on CD14 expression in vitro, we evaluated CD14 expression in response to LPS with a fully differentiated macrophage phenotype, the alveolar macrophage. By using flow microfluorometric analysis and a radioimmunoassay with an anti-human CD14 monoclonal antibody (My4) that cross-reacts with porcine CD14, we found that macrophages stimulated with LPS for 24 h exhibited a two- to fivefold increase in CD14-like antigen compared with unstimulated cells. At low concentrations of LPS, up-regulation of the CD14-like antigen was dependent on serum; at higher concentrations of LPS, serum was not required. In the absence of serum a 10-fold higher dose of LPS (10 ng/ml) was required to increase CD14-like expression. In addition, LPS-induced CD14-like up-regulation correlated with secretion of tumor necrosis factor-alpha, regardless of serum concentration. Blockade with My4 antibody significantly inhibited LPS-induced tumor necrosis factor-alpha secretion at 1 ng/ml of LPS. However, inhibition decreased as we increased the LPS concentration, suggesting the existence of CD14-independent pathways of macrophage activation in response to LPS. Alternatively, My4 may have a lower affinity for the porcine CD14 antigen than LPS, which may have only partially blocked the LPS-LBP binding site at high concentrations of LPS. Therefore, these data suggest that LPS activation of porcine alveolar macrophages for 24 h increased CD14-like receptor expression. The degree of CD14-like up-regulation was related to LPS concentration, however, activation did not require the presence of serum at high concentrations of LPS.

Biliary glycoprotein, a potential human cell adhesion molecule, is down-regulated in colorectal carcinomas.

Biliary glycoprotein (BGP) is the human homologue of a cell adhesion molecule (CAM) of the rat designated Cell-CAM. The BGP gene is a member of the carcinoembryonic antigen gene family, which belongs to the immunoglobulin superfamily. BGP is expressed in cells of epithelial and myeloid origin. In granulocytes, BGP is a main antigen of the CD66 cluster of differentiation antigens that mediate the binding to endothelial E-selectin. Since BGP is a major human CAM, the expression of BGP was studied in 21 colorectal carcinoma tissue specimens and in the respective adjacent normal mucosae. As an internal control for epithelial mRNA, the expression of cytokeratin 18 was evaluated in parallel. In addition, the expression of carcinoembryonic antigen and nonspecific crossreacting antigen, which are highly homologous to BGP, was investigated. Two BGP mRNAs of 3.9 and 1.5 kilobases were detected in the normal colonic mucosa samples. The median of the tumor-to-normal ratios of mRNA expression was 0.2 for both BGP mRNAs. In contrast, the median was 1.2 for cytokeratin, 1.0 for carcinoembryonic antigen, and 1.4 for nonspecific crossreacting antigen. Relative to cytokeratin 18 expression, the expression of BGP was reduced to < or = 0.1 in half of the tumors and to < or = 0.4 in > 80% of the tumors. These findings indicate that the loss or reduced expression of the adhesion molecule BGP is a major event in colorectal carcinogenesis.

Immunohistochemical distribution of leucocyte antigens in lymphoid tissues of cynomolgus monkeys (Macaca fascicularis)

Crossreactivity of antibodies to human leucocyte antigens with lymphoid tissues of cynomolgus monkeys was studied by immunohistochemistry and immunoblotting. Of a total of 54 clusters of differentiation (CD) antigens, 39 were expressed essentially with the same immunostaining patterns in the monkey as in human lymphoid tissues. By immunoblotting L26 (CD20) detected a 35 Kd molecule in the monkey lymph node. Our observations indicated that most of the CD antigens are expressed and can be studied in lymphoid tissues of cynomolgus monkeys.

Expression of CD59, a Human Complement System Regulatory Protein, in Extraembryonic Membranes

CD59 (leukocyte cluster of differentiation antigen 59), is a phosphatidylinositol glycan-anchored membrane protein that inhibits lysis of cells by terminal complement system components. To further define complement regulatory proteins relevant to pregnancy, this study characterized the expression of CD59 in human extraembryonic membranes. Immunohistology with CD59 monoclonal antibody MEM-43 showed that this molecule was normally present on the apical surface of the syncytiotrophoblast, on extravillous cytotrophoblast, and amniotic epithelium. Immunoblotting confirmed that first and second trimester syncytiotrophoblast microvilli (STM) contained a glycoprotein similar in mass and glycosylation to CD59 from adult cells and tissues. Reactivities of STM with MEM-43 in ELISA were 2- to 6-fold higher than those of kidney, erythrocyte and platelet membranes. Term placental STM from recurrent spontaneous aborting patients after immunotherapy, reacted with MEM-43 in ELISA similarly to STM from normal individuals. Plasmas from pregnant women and umbilical cords had 50% or greater reactivity with MEM-43 than did normal plasmas. CD59 could help protect extraembryonic epithelia from damage by complement in maternal blood and amniotic fluid. The apical location of CD59 reflects the immunological roles and functional polarization of plasma membranes in the syncytiotrophoblast.

Repeated restraint and isolation stress alters adrenal and lymphocyte functions and some leukocyte differentiation antigens in lambs.

Lambs were used to evaluate the effect of repeated restraint and isolation stress (RIS) on secretion of cortisol, lymphocyte proliferative responses to mitogens, production of interleukin-2, and expression of leukocyte differentiation antigens. Differentiation antigens evaluated included cluster of differentiation antigens 2, 4, and 8 (CD2, CD4, and CD8, respectively); B cells; and major histocompatibility complex (MHC) class II, DQ, and DR. Lambs were assigned to either control (CON; n = 12) or to RIS treatment (n = 12) then were stanchioned in environmentally controlled rooms at 18 degrees C and constant light for 11 d before jugular vein catheters were inserted on d 0 of the experiment. On d 12, 13, and 14, lambs in the RIS treatment were removed to another location, restrained, and isolated from visual and tactile contact with other lambs for 6 h on each day. Following the 6-h stress treatment, lambs were returned to their home stanchions. The CON lambs remained in their stanchions. Samples of serum were obtained from all lambs, beginning before RIS (0 h) and at .5-h intervals until the completion of stress (6 h) on d 12 and 14. In addition, samples of whole blood were obtained at 0 and 6 h on d 12, 13, and 14 for evaluation of immune function characteristics. Fitted polynomial curves describing the cortisol response in RIS and CON lambs differed (P less than .005) on both d 12 and 14, reflecting the unmistakable increase in cortisol in response to the stressor.(ABSTRACT TRUNCATED AT 250 WORDS)

The human leukocyte‐adhesion ligand, intercellular‐adhesion molecule 2

The leukocyte cell-adhesion receptors, complexes of the cluster of differentiation antigen 11a with cluster of differentiation antigen 18 (CD11a/CD18), cluster of differentiation antigen 11b with cluster of differentiation antigen 18 (CD11b CD18) and cluster of differentiation antigen 11c with cluster of differentiation antigen 18 (CD11c CD18), are of major importance in several leukocyte functions. Previously a cellular ligand named intercellular-adhesion molecule 1 (ICAM-1) was identified, isolated and extensively characterized. Recently a second similar molecule, intercellular-adhesion molecule 2 (ICAM-2), was found by a functional DNA-cloning method. We have now synthesized the ICAM-2 DNA by the polymerase chain reaction (PCR), sequenced it, and transferred it into mammalian and bacterial expression vectors. A functional leukocyte-binding glycoprotein was obtained by transfection of COS-1 cells. A soluble protein-A - ICAM-2 fusion protein was made in Escherichia coli, purified and used for antiserum production. The antiserum precipitated a cell-surface protein with an apparent molecular mass of 55 kDa from ICAM-2 transfected COS-1 cells, leukocytes and endothelial cells, and inhibited leukocyte binding to transfected COS-1 cells. The bacterial fusion protein, lacking carbohydrate, specifically bound to leukocyte receptors.

Human epidermal basal keratinocytes express CDw29 antigens

Two monoclonal antibodies, K20 and 4B4, assigned to the CDw29 cluster of differentiation antigens, were shown to react with basal keratinocytes (BK). The aim of this study was to identify the antigens recognized by K20 and 4B4 on epidermal cells, and to determine whether they were identical to those found on lymphocytes. Basal keratinocyte-enriched cell suspensions were labelled with 125I and then 1% NP40 cell lysates were used for immunoprecipitation. Under reducing conditions, K20 and 4B4 immunoprecipitated from basal keratinocytes a broad MW 105,000 band and proteins of MW 145,000, 90,000 and 80,000. Under non-reducing conditions, each band was shifted down by approximately 5000 MW. Metabolic labelling studies demonstrated that the MW 145,000 and 105,000 subunits were synthesized by basal keratinocytes. On lymphoid cells, K20 and 4B4 are known to precipitate glycoprotein complexes made of a broad MW 130,000 protein band (beta subunit) associated with a protein of MW 150,000 (alpha subunit) and proteins of MW 90,000 and 80,000 expressed in very low amounts. The MW 145,000 and 105,000 bands immunoprecipitated by K20 from basal keratinocytes correspond to the alpha and beta subunits present on lymphoid cells. It has recently been demonstrated that K20 recognizes the common beta subunit of the very late antigens family (VLA) and that 4B4 defines the helper-inducer subset of T lymphocytes. The present investigation provides evidence that basal keratinocytes share antigens of the VLA family with lymphoid cells and that they play an important role in the immune response in the skin-immune system.