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PubMed2003

Transfection of IL-10 expression vectors into endothelial cultures attenuates alpha4beta7-dependent lymphocyte adhesion mediated by MAdCAM-1.

BACKGROUND: Enhanced expression of MAdCAM-1 (mucosal addressin cell adhesion molecule-1) is associated with the onset and progression of inflammatory bowel disease. The clinical significance of elevated MAdCAM-1 expression is supported by studies showing that immunoneutralization of MAdCAM-1, or its ligands reduce inflammation and mucosal damage in models of colitis. Interleukin-10 (IL-10) is an endogenous anti-inflammatory and immunomodulatory cytokine that has been shown to prevent inflammation and injury in several animal studies, however clinical IL-10 treatment remains insufficient because of difficulties in the route of IL-10 administration and its biological half-life. Here, we examined the ability of introducing an IL-10 expression vector into endothelial cultures to reduce responses to a proinflammatory cytokine, TNF-alpha METHODS: A human IL-10 expression vector was transfected into high endothelial venular ('HEV') cells (SVEC4-10); we then examined TNF-alpha induced lymphocyte adhesion to lymphatic endothelial cells and TNF-alpha induced expression of MAdCAM-1 and compared these responses to control monolayers. RESULTS: Transfection of the IL-10 vector into endothelial cultures significantly reduced TNF-alpha induced, MAdCAM-1 dependent lymphocyte adhesion (compared to non-transfected cells). IL-10 transfected endothelial cells expressed less than half (46 +/- 6.6%) of the MAdCAM-1 induced by TNF-alpha (set as 100%) in non-transfected (control) cells. CONCLUSION: Our results suggest that gene therapy of the gut microvasculature with IL-10 vectors may be useful in the clinical treatment of IBD.

Adhesiveness↗
PubMed2006

Arrhythmogenic right ventricular cardiomyopathy type 6 (ARVC6): support for the locus assignment, narrowing of the critical region and mutation screening of three candidate genes.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable disorder characterized by progressive degeneration of right ventricular myocardium, arrhythmias and an increased risk of sudden death at a young age. By linkage analysis, ARVC type 6 was previously mapped to a 10.6 cM region on chromosome 10p12-p14 in a large North American kindred. To date, the genetic defect that causes ARVC6 has not been identified. METHODS: We identified a South African family of 13 members with ARVC segregating as an autosomal dominant disorder. The diagnosis of ARVC was based on international diagnostic criteria. All available family members were genotyped with microsatellite markers at six known ARVC loci, and positional candidate gene screening was performed. RESULTS: Genetic linkage and haplotype analysis provided lod scores that are highly suggestive of linkage to the ARVC6 locus on chromosome 10p12-p14, and the narrowing of the critical region to approximately 2.9 Mb. Two positional candidate genes (ITG8 and FRMD4A) were screened in which defects could possibly disrupt cell-cell adhesion. A non-positional candidate gene with apoptosis inducing properties, LAMR1P6 (laminin receptor 1 pseudogene 6) was also screened. Direct sequencing of DNA from affected individuals failed to detect disease-causing mutations in the exonic sequences of the three genes investigated. CONCLUSION: The narrowing of the ARVC6 critical region may facilitate progress towards the identification of the gene that is involved in ARVC. Identification of the causative genes for ARVC will contribute to the understanding of the pathogenesis and management of this poorly understood condition.

Adolescent↗
PubMed2004

CCL25 enhances CD103-mediated lymphocyte adhesion to E-cadherin.

Our results demonstrate that (1) CD103 is upregulated on CD8(+) T cells subsequent to their entry into the small intestinal epithelium, and (2) that the chemokine CCL25 enhances CD103-mediated adhesion to E-cadherin. These results suggest a novel role for chemokines in modulating interactions between lymphocytes and epithelial cells at mucosal surfaces.

Adoptive Transfer↗
PubMed2001

A novel C-type lectin regulating cell growth, cell adhesion and cell differentiation of the multipotent epithelium in budding tunicates.

We have isolated two Ca(2+)-dependent, galactose-binding polypeptides from the budding tunicate, Polyandrocarpa misakiensis. Based on their partial amino acid sequences, full-length cDNAs were cloned. One of them was identical with a tunicate C-type lectin (TC14-2) reported previously. The other was a novel C-type lectin, referred to as TC14-3. In living animals, they appeared to be coupled. This complex of lectins, when applied in vitro to tunicate multipotent cells of epithelial origin, blocked cell proliferation and induced cell aggregation. The aggregates expressed a homolog of the integrin alpha-chain and other differentiation markers specific for epithelial cells. Recombinant TC14-3 could reproduce all the activities of native lectins by itself, which was accelerated by recombinant TC14-2. The inhibitory activity of TC14-3 on cell growth was completely abolished by the addition of 50 microM D-galactose. Anti-TC14-3 monoclonal antibody showed that the antigen was expressed constitutively by the multipotent epithelial and mesenchymal cells. These results provide evidence that in P. misakiensis a C-type lectin plays a novel, cytostatic role in regulating cell growth, cell adhesion and cell differentiation during asexual reproduction.

Amino Acid Sequence↗
PubMed2002

Defects in keratinocyte activation during wound healing in the syndecan-1-deficient mouse.

Mice lacking syndecan-1 are viable, fertile and have morphologically normal skin, hair and ocular surface epithelia. While studying the response of these mice to corneal epithelial and skin wounding, we identified defects in epithelial cell proliferation and regulation of integrin expression. mRNA profiling of corneal epithelial tissues obtained from wild-type and syndecan-1(-/-) mice suggest that these defects result from differences in overall gene transcription. In the cornea, syndecan-1(-/-) epithelial cells migrate more slowly, show reduced localization of alpha9 integrin during closure of wounds and fail to increase their proliferation rate 24 hours after wounding. In the skin, we did not document a migration defect after full thickness wounds but did observe cell proliferation delays and reduced localization of alpha9 integrin in the syndecan-1(-/-) epidermis after dermabrasion. Despite increased cell proliferation rates in the uninjured syndecan-1(-/-) epidermis and the corneal epithelium, morphologically normal epithelial thickness is maintained prior to injury; however, wounding is accompanied by prolonged hypoplasia in both tissues. Analyses of integrin protein levels in extracts from full thickness skin, revealed increased levels of alpha3 and alpha9 integrins both prior to injury and after hair removal in syndecan-1(-/-) mice but no increase 2 days after dermabrasion. These data for the first time show involvement of alpha9 integrin in skin wound healing and demonstrate essential roles for syndecan-1 in mediating cell proliferation and regulation of integrin expression in normal and wounded epithelial tissues.

Animals↗
PubMed2002

E-cadherin-mediated interactions of thymic epithelial cells with CD103+ thymocytes lead to enhanced thymocyte cell proliferation.

Cadherins are a family of cell adhesion molecules that mainly mediate homotypic homophilic interactions, but for E-cadherin, heterophilic interactions with the integrin alpha(E)(CD103)beta(7) have also been reported. In the human thymus, where thymocytes develop in close contact with thymic stromal cells, E-cadherin expression was detected on thymic epithelial cells. By immunofluorescence staining, the strongest expression of E-cadherin was observed on medullary thymic epithelial cells. These cells also express cytosolic catenins, which are necessary to form functional cadherin-catenin complexes. Regardless of their developmental stage, human thymocytes do not express E-cadherin, indicating that homophilic interactions cannot occur. Flow cytometric analysis revealed that the E-cadherin ligand CD103 is expressed on subpopulations of the early CD4(-) CD8(-) double-negative and of the more mature CD8(+) single-positive thymocytes. Using an in vitro cell adhesion assay, double-negative and CD8(+) single-positive thymocytes adhered strongly to isolated thymic epithelial cells. These adhesive interactions could be inhibited by antibodies against E-cadherin or CD103. CD8(+) thymocytes showed a proliferative response when incubated with thymic epithelial cells. This mitogenic effect was inhibited by antibodies against CD103, which strongly indicates a direct involvement of the adhesive ligand pair CD103-E-cadherin in human thymocyte cell proliferation.

Antigens, CD↗
PubMed1997

Functional expression of the alpha 7 integrin receptor in differentiated smooth muscle cells.

Expression of the alpha7 integrin is developmentally regulated and is thought to be tissue-specific for both skeletal and cardiac muscles. We now report that alpha7 is also strongly and ubiquitously expressed by various types of smooth muscle, including vascular, gastrointestinal and genitourinary smooth muscles. In addition, alpha7 was surface-expressed by a number of smooth muscle cell lines that maintained their differentiated phenotype following adaptation to culture. Studies with the mouse 9E11G smooth muscle cell line showed that the alpha7 integrin mediated both adhesion and motility of these cells on laminin 1 substrates. Alpha7 expression appears to correlate with the smooth-muscle-differentiated phenotype. The multipotential P19 mouse embryonic stem cell line lacks alpha7 but uses the alpha6 integrin to adhere to laminin 1. Following retinoic acid-induced P19 differentiation predominantly to the smooth muscle cell lineage, high expression of alpha7 was detected along with partial dependence on alpha7 for binding to laminin. The expression of alpha7 paralleled the induction of smooth-muscle-specific alpha-actin, as revealed by dual-labeling flow cytometry. In contrast, alpha7, which initially was highly expressed on the surface of vascular smooth muscle cell explants, was rapidly downregulated in smooth muscle cell outgrowths as they dedifferentiated into their synthetic phenotype. The results indicate that the expression of alpha7 integrin in smooth muscle cells is associated with their differentiated phenotype and mediates their interaction with laminins.

Amino Acid Sequence↗
PubMed2006

Immunophenotypic variations in hairy cell leukemia.

Hairy cell leukemia (HCL) exhibits a characteristic immunophenotypic profile that is strongly positive for pan-B-cell markers; positive for CD103, CD11c. and CD25; and usually negative for CD5, CD10, and CD23. We evaluated 35 HCL cases and identified atypical immunophenotypes in 12 cases (34%), including CD103- in 2 (6%), CD25- in 1 (3%), CD10+ in 5 (14%), and CD23+ in 6 (17%) cases. Among these cases one was CD103-/CD10+ and one was CD10+/CD23+. All available specimens from the 12 cases were reviewed and showed morphologic features characteristic for HCL. The initial clinical information was reviewed and showed no significant differences with that reported for typical HCL. Of the 12 cases, 11 patients received purine analogue therapy and achieved complete remissions. Our study indicates that it is not uncommon for HCL to display an unusual immunophenotype, including negativity for CD103 or CD25. Recognizing the variability of immunophenotype and correlating with morphologic and clinical features are essential for establishing an accurate diagnosis of HCL.

Adult↗
PubMed2006

Foxp3-expressing CD103+ regulatory T cells accumulate in dendritic cell aggregates of the colonic mucosa in murine transfer colitis.

Little is known of the anatomical compartmentalization of colitogenic or regulatory T-cell responses in the murine transfer colitis model. Therefore, we analyzed the putative function of large intestinal dendritic cell (DC) aggregates, to which donor CD4+ T cells selectively home before colitis becomes manifest. The co-stimulatory molecules MHC-II, CD40, CD80, and CD86 were expressed in DC aggregates. IL-23 was primarily absent from DC aggregates at all stages of disease but was expressed at high levels in the severely inflamed lamina propria. Interferon-gamma was up-regulated in the lamina propria during early and advanced disease, whereas in DC aggregates it was detectable to a significant degree only in fully developed colitis. In contrast, Foxp3, a marker of regulatory T cells, was expressed in DC aggregates on T-cell transfer, coinciding with the appearance of CD103+ CD25- T cells in these clusters. Foxp3 was enriched in the CD103+ T-cell fraction isolated from the lamina propria of diseased mice. T-cell grafts depleted of CD103+ T cells generated similar numbers of colonic CD103+ T cells as unfractionated T cells. We conclude that DC aggregates are structures involved in the expansion and/or differentiation of CD103+ CD25- CD4+ Foxp3-expressing regulatory T cells.

Animals↗
PubMed2006

Expression of beta2-integrin on leukocytes in liver cirrhosis.

AIM: To analyze beta2-integrin expression on blood leukocytes in liver cirrhosis. METHODS: In 40 patients with liver cirrhosis and 20 healthy individuals, the evaluation of expression of CD11a (LFA-1alpha), CD11b (Mac-1alpha), CD11c (alphaX) and CD49d (VLA-4alpha) on peripheral blood leukocytes was performed using flow cytometry. The analysis was carried out in groups of patients divided into B and C according to Child-Pugh's classification. RESULTS: An increased CD11a, CD11b, CD11c and CD49d integrin expression was observed on peripheral blood leukocytes in liver cirrhosis. The integrin levels were elevated as the advancement of liver failure progressed. The highest expression of integrins occurred predominantly on monocytes. A slight expression of VLA-4 was found on lymphocytes and granulocytes and it increased together with liver failure. A positive correlation was noted between median intensity of fluorescence (MIF) expression on polymorphonuclear cells of CD11a and CD11c and CD49d (r = 0.42, P < 0.01; r = 053, P < 0.01, respectively) in liver cirrhosis stage C. However, no correlation was observed between integrin expression on leukocytes. The concentrations of sICAM-1, sVCAM-1, and TNFalpha, were significantly elevated in liver cirrhosis. CONCLUSION: beta2-integrin expression on leukocytes increases in liver cirrhosis decompensated as the stage of liver failure increases, which is a result of permanent activation of leukocytes circulating through the inflamed liver environment. beta2-integrin expression on circulating leukocytes can intensify liver cirrhosis.

Adult↗
PubMed2001

Cutting edge: dichotomy of homing receptor dependence by mucosal effector B cells: alpha(E) versus L-selectin.

The common mucosal immune system may be compartmentalized because lymphocyte homing to the upper respiratory tract appears to be mediated by L-selectin interactions rather than alpha(4)beta(7) interactions, as is the case for gut-associated lymphoreticular tissue. To assess the role of L-selectin in effector B cell immunity, L-selectin-deficient mice were intranasally immunized with cholera toxin (CT), and mucosal immune responses were compared with C57BL/6 mice. The absence of L-selectin correlated with a reduction in CT-specific secretory-IgA responses in nasal passages and reproductive tract, but not intestinal lamina propria. Cell sorting experiments showed that an L-selectin-dependent subset was responsible for CT-specific responses in nasal passages and reproductive tract, whereas an alpha(E)beta(7)(+) B cell subset was responsible for L-selectin-independent intestinal immunity. This study provides evidence for compartmentalization of the common mucosal immune system into "intestinal" vs "nonintestinal" effector sites.

Animals↗
PubMed2003

T cells of atopic asthmatics preferentially infiltrate into human bronchial xenografts in SCID mice.

T cells play an important role in the pathogenesis of bronchial asthma. However, it is not completely known how circulating lymphocytes infiltrate into the airways of asthmatic patients. Because SCID mice are unable to reject xenogenic transplants, many xenotransplant models using various human tissues have been developed. Therefore, to examine the interaction between bronchi and T lymphocytes of asthma, it may be possible to use the human bronchial xenograft and PBMC xenograft in SCID mice. We transplanted human bronchi into the subcutaneum of SCID mice and i.p. injected PBMCs that were obtained from patients with atopic asthma, atopic dermatitis and rheumatoid arthritis, and normal subjects (asthmatic, dermatitis, rheumatic, and normal huPBMC-SCID mice). There was no difference in the percentage of CD3-, CD4-, CD8-, CD25-, CD45RO-, CD103-, and cutaneous lymphocyte Ag-positive cells in PBMCs among the patients with asthma, dermatitis, rheumatoid arthritis, and normal subjects, and CD3-positive cells in peripheral blood of asthmatic, dermatitis, rheumatic, and normal huPBMC-SCID mice. The number of CD3-, CD4-, and CD8-positive cells in the xenografts of asthmatic huPBMC-SCID mice was higher than those of dermatitis, rheumatic, and normal huPBMC-SCID mice. IL-4 mRNA and IL-5 mRNA were significantly higher in the xenografts of asthmatic huPBMC-SCID mice than those in the xenografts of normal huPBMC-SCID mice, but there were no significant differences in the expressions of IL-2 mRNA or IFN-gamma mRNA between them. These findings suggest that T cells, especially Th2-type T cells, of asthmatics preferentially infiltrate into the human bronchi.

Animals↗
PubMed2004

Regulation of CD103 expression by CD8+ T cells responding to renal allografts.

CD103 is an integrin with specificity for the epithelial cell-specific ligand, E-cadherin. Recent studies indicate that CD103 expression endows peripheral CD8 cells with a unique capacity to access the epithelial compartments of organ allografts. In the present study we used a nonvascularized mouse renal allograft model to 1) define the mechanisms regulating CD103 expression by graft-infiltrating CD8 effector populations, and 2) identify the cellular compartments in which this occurs. We report that CD8 cells responding to donor alloantigens in host lymphoid compartments do not initially express CD103, but dramatically up-regulate CD103 expression to high levels subsequent to migration to the graft site. CD103+CD8+ cells that infiltrated renal allografts exhibited a classic effector phenotype and were selectively localized to the graft site. CD8 cells expressing low levels of CD103 were also present in lymphoid compartments, but three-color analyses revealed that these are almost exclusively of naive phenotype. Adoptive transfer studies using TCR-transgenic CD8 cells demonstrated that donor-specific CD8 cells rapidly and uniformly up-regulate CD103 expression following entry into the graft site. Donor-specific CD8 cells expressing a dominant negative TGF-beta receptor were highly deficient in CD103 expression following migration to the graft, thereby implicating TGF-beta activity as a dominant controlling factor. The relevance of these data to conventional (vascularized) renal transplantation is confirmed. These data support a model in which TGF-beta activity present locally at the graft site plays a critical role in regulating CD103 expression, and hence the epitheliotropism, of CD8 effector populations that infiltrate renal allografts.

Animals↗
PubMed2004

Murine CD8+ recent thymic emigrants are alphaE integrin-positive and CC chemokine ligand 25 responsive.

Recent thymic emigrants (RTE) are an important subpopulation of naive CD8+ T cells because of their ability to reconstitute a diverse immune system after periods of T cell depletion. In neonatal mice, the majority of peripheral T lymphocytes are RTE, cells that have recently left the thymus to populate the periphery. Postulating that these cells could have unique trafficking mechanisms, we compared adhesion molecule and chemokine receptor expression of neonatal RTE with mature adult lymphocytes. Neonatal CD8+ splenocytes uniformly express alpha(E) integrin and exhibit a high responsiveness to CC chemokine ligand (CCL25) (as compared with adult CD8+ splenocytes). Mature CD8+ thymocytes have a similar alpha(E) integrin(+) CCL25 responsive phenotype, as do adult CD8+ RTE identified by intrathymic FITC injection. With increasing age, the frequency of CD8+ alpha(E) integrin(+) splenocytes decreases, roughly correlating with thymic involution. Moreover, halting thymic output by thymectomy accelerates the age-dependent decline in peripheral CD8+ alpha(E) integrin(+) RTE phenotype cells. Low expression of CD44 distinguishes these CD8+ RTE from a population of memory phenotype alpha(E) integrin(+) CD8+ cells that are CD44(high). We conclude that CD8+ RTE have unique adhesive and chemotactic properties that distinguish them from naive CD8+ T cells. These properties may enable specialized microenvironmental and cell-cell interactions contributing to the fate of RTE in the periphery during the early post-thymic period. This phenotype will also facilitate the identification and isolation of RTE for further studies.

Age Factors↗
PubMed2004

Deficiency of CD11b or CD11d results in reduced staphylococcal enterotoxin-induced T cell response and T cell phenotypic changes.

The beta(2) integrin CD11a is involved in T cell-APC interactions, but the roles of CD11b, CD11c, and CD11d in such interactions have not been examined. To evaluate the roles of each CD11/CD18 integrin in T cell-APC interactions, we tested the ability of splenocytes of CD11-knockout (KO) mice to respond to staphylococcal enterotoxins (SEs), a commonly used superantigen. The defect in T cell proliferation with SEA was more severe in splenocytes from mice deficient in CD18, CD11b, or CD11d than in CD11a-deficient splenocytes, with a normal response in CD11c-deficient splenocytes. Mixing experiments showed that the defect of both CD11b-KO and CD11d-KO splenocytes was, unexpectedly, in T cells rather than in APC. Cytometric analysis failed to detect CD11b or CD11d on resting or activated T cells or on thymocytes of wild-type adult mice, nor did Abs directed to these integrins block responses in culture, suggesting that T cells educated in CD11b-KO or CD11d-KO mice were phenotypically altered. Consistent with this hypothesis, T cells from CD11b-KO and CD11d-KO splenocytes exhibited reduced intensity of CD3 and CD28 expression and decreased ratios of CD4/CD8 cells, and CD4(+) T cells were reduced among CD11b-KO and CD11d-KO thymocytes. CD11b and CD11d were coexpressed on a subset of early wild-type fetal thymocytes. We postulate that transient thymocyte expression of both CD11b and CD11d is nonredundantly required for normal thymocyte and T cell development, leading to phenotypic changes in T cells that result in the reduced response to SE stimulation.

Animals↗
PubMed2005

Peptide-specific CD8 T regulatory cells use IFN-gamma to elaborate TGF-beta-based suppression.

We identified a murine peptide-specific CD8 T regulatory cell population able to suppress responding CD4 T cells. Immunization with OVA, poly(I:C), and anti-4-1BB generated a population of SIINFEKL-specific CD8 T regulatory cells that profoundly inhibited peptide-responding CD4 T cells from cellular division. The mechanism of suppression required IFN-gamma, but IFN-gamma alone was not sufficient to suppress the responding CD4 T cells. The data show that CD8 T regulatory cells were unable to suppress unless they engaged IFN-gamma. Furthermore, even in the absence of recall with peptide, the CD8 T regulatory cells suppressed CD4 responses as long as IFN-gamma was present. To examine the effector mechanism of suppression, we showed that neutralizing TGF-beta inhibited suppression because inclusion of anti-TGF-beta rescued the proliferative capacity of the responding cells. TGF-beta-based suppression was dependent completely upon the CD8 T regulatory cells being capable of binding IFN-gamma. This was the case, although peptide recall of primed IFN-gamma (-/-) or IFN-gammaR(-/-) CD8 T cells up-regulated pro-TGF-beta protein as measured by surface latency-associated peptide expression but yet were unable to suppress. Finally, we asked whether the CD8 T regulatory cells were exposed to active TGF-beta in vivo and showed that only wild-type CD8 T regulatory cells expressed the TGF-beta-dependent biomarker CD103, suggesting that latency-associated peptide expression is not always congruent with elaboration of active TGF-beta. These data define a novel mechanism whereby IFN-gamma directly stimulates CD8 T regulatory cells to elaborate TGF-beta-based suppression. Ultimately, this mechanism may permit regulation of pathogenic Th1 responses by CD8 T regulatory cells.

Animals↗
PubMed2005

Runx3 regulates integrin alpha E/CD103 and CD4 expression during development of CD4-/CD8+ T cells.

During thymic T cell development, immature CD4+CD8+ double-positive (DP) thymocytes develop either into CD4+CD8- Th cells or CD4-CD8+ CTLs. Differentially expressed primary factors inducing the fate of these cell types are still poorly described. The transcription factor Runx3/AML-2 Runx, runt [corrected] dominant factor; AML, acute myeloid leukemia is expressed specifically during the development of CD8 single-positive (SP) thymocytes, where it silences CD4 expression. Deletion of murine Runx3 results in a reduction of CD8 SP T cells and concomitant accumulation of CD4+CD8+ T cells, which cannot down-regulate CD4 expression in the thymus and periphery. In this study we have investigated the role of Runx3 during thymocyte development and CD4 silencing and have identified integrin alpha(E)/CD103 on CD8 SP T cells as a new potential target gene of Runx3. We demonstrate that Runx3 is necessary not only to repress CD4, but also to induce CD103 expression during development of CD8 SP T cells. In addition, transgenic overexpression of Runx3 reduced CD4 expression during development of DP thymocytes, leading to a reduced number of CD4 SP thymocytes and an increased number of CD8 SP thymocytes. This reversal is not caused by redirection of specific MHC class II-restricted cells to the CD8 lineage. Overexpression of Runx3 also up-regulated CD103 expression on a subpopulation of CD4 SP T cells with characteristics of regulatory T cells. Thus, Runx3 is a main regulator of CD4 silencing and CD103 induction and thus contributes to the phenotype of CD8 SP T cells during thymocyte development.

Amino Acid Sequence↗
PubMed2005

Immature CD4- CD103+ rat dendritic cells induce rapid caspase-independent apoptosis-like cell death in various tumor and nontumor cells and phagocytose their victims.

We previously reported the characterization of a MHC class II(low) CD4- CD103+ (CD4-) subset of dendritic cells (DC) in rat spleen that exhibit a Ca2+-, Fas ligand-, TRAIL- and TNF-alpha-independent cytotoxic activity against specific targets in vitro. In this study, we demonstrate that this DC subset was also found in lymph nodes. Freshly extracted and, therefore, immature CD4- DC exhibited a potent cytotoxic activity against a large panel of tumor cell lines as well as primary endothelial cells. The cytotoxic activity of immature CD4- DC required cell-to-cell contact and de novo protein expression. CD4- DC-mediated cell death resembled apoptosis, as evidenced by outer membrane phosphatidylserine exposure and nuclear fragmentation in target cells, but was caspase as well as Fas-associated death domain and receptor-interacting protein independent. Bcl-2 overexpression in target cells did not protect them against DC-mediated cell death. Immature CD4- DC phagocytosed efficiently apoptotic cells in vitro and, therefore, rapidly and specifically engulfed their victims following death induction. Maturation induced a dramatic down-regulation of the killing and phagocytic activities of CD4- DC. In contrast, CD4+ DC were both unable to kill target cells and to phagocytose apoptotic cells in vitro. Taken together, these data indicate that rat immature CD4- CD103+ DC mediate an unusual cytotoxic activity and can use this function to efficiently acquire Ag from live cells.

Adaptor Proteins, Signal Transducing↗