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PubMed2003

CD103 mRNA levels in urinary cells predict acute rejection of renal allografts.

BACKGROUND: CD103 is displayed on the cell surface of alloreactive CD8 cytotoxic T lymphocytes (CTLs) and is a critical component for the intraepithelial homing of T cells. Because intratubular localization of mononuclear cells is a feature of acute cellular rejection of renal allografts, we explored the hypothesis that CD103 messenger (m)RNA levels in urinary cells predict acute rejection. METHODS: We collected 89 urine specimens from 79 recipients of renal allografts. RNA was isolated from the urinary cells, and we measured CD103 mRNA levels and a constitutively expressed 18S ribosomal (r)RNA with the use of real-time quantitative polymerase chain reaction assay. RESULTS: CD103 mRNA levels, but not 18S rRNA levels, were higher in urinary cells from 30 patients with an episode of acute rejection (32 biopsies and 32 urine samples) compared with the levels in 12 patients with other findings on allograft biopsy (12 biopsies and 12 urine samples), 12 patients with biopsy evidence of chronic allograft nephropathy (12 biopsies and 12 urine samples), and 25 patients with stable graft function after renal transplantation (0 biopsies and 33 urine samples) (P = 0.001; one-way analysis of variance). Acute rejection was predicted with a sensitivity of 59% and a specificity of 75% using natural log-transformed value 8.16 CD103 copies per microgram as the cutoff value (P = 0.001). CONCLUSION: CD103 mRNA levels in urinary cells are diagnostic of acute rejection of renal allografts. Because CD103 is a cell surface marker of intratubular CD8 CTLs, a noninvasive assessment of cellular traffic into the allograft may be feasible by the measurement of CD103 mRNA levels in urinary cells.

Acute Disease↗
PubMed2001

Flow cytometry of peripheral blood and bone marrow cells from patients with hairy cell leukemia: phenotype of hairy cells, lymphocyte subsets and detection of minimal residual disease after treatment.

By flow cytometry (FC) and an extensive panel of markers we characterized leukemia cells from the peripheral blood (PB) and bone marrow (BM) of 13 symptomatic patients with hairy cell leukemia (HCL). Hairy cells (HCs) identified in the large cell gate always expressed B-cell markers - CD19, CD20, CD22, HLA-DR, and 'HCL-restricted' markers - CD22+CD11c, CD25 and CD103. Other markers, not followed regularly, were occasionally expressed, such as CD34, CD38, CD71, CD15, CD10 and kappa/lambda light chains. Furthermore, in one patient with suspect but not proved HCL in PB or BM, neither morphologically nor immunologically, we confirmed the diagnosis of HCL. Only the immunophenotyping of splenic cells after splenectomy confirmed HCL diagnosis. Flow cytometry was repeated at 3-5 month intervals, after treatment with 2-Chlorodeoxyadenosine (CdA) or less frequently alpha-interferon (IFN). We investigated serially lymphocyte subsets after treatment and we found profound and persistent CD4+ lymphopenia in majority of studied patients after CdA treatment. Simultaneously we investigated the value of FC to detect minimal residual disease (MRD) and to establish, whether MRD+ could predict relapse. Detection of MRD in our series predicted hematological relapse only in one case with persistent MRD+, in majority of cases with occasionally found MRD+ phenotype, did not. Using quantitative immunophenotyping we observed significantly higher values of molecule numbers of hairy cell B-cell markers, comparing to B-cells in nonleukemic gate of the same sample. Our study showed 1) the diagnostic value of FC in management of HCL patients, 2) long-lasting response in the majority of patients after CdA, 3) a profound and persistent CD4+ lymphopenia in CdA treated patients, 4) some correlation between persistent MRD staining and hematological relapse, and 5) further, till now not described activated feature of HCs, given by the increased values of molecular numbers (molecules of equivalent soluble fluoresceine - MESF) in B-cell antigens of HCL.

Adult↗
PubMed2003

Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease.

BACKGROUND & AIMS: The mechanism of intraepithelial lymphocyte hyperplasia, a hallmark of celiac disease, is unknown. We have investigated the role of epithelium-derived interleukin (IL)-15 in the alterations of epithelial homeostasis in refractory celiac sprue, a privileged situation to study the first step of lymphoid transformation and the contribution of intraepithelial lymphocytes to villous atrophy in celiac disease. METHODS: IL-15 expression was assessed in biopsy specimens and isolated enterocytes by combining immunohistochemistry, flow cytometry, and real-time quantitative polymerase chain reaction. The ability of IL-15 to induce growth and survival of clonal intraepithelial lymphocytes lacking surface CD3 and to induce their cytotoxicity and secretion of interferon gamma was tested using soluble IL-15 and coculture in the presence of epithelial cell lines expressing membrane IL-15. RESULTS: IL-15 was massively overexpressed not only in lamina propria but also in the intestinal epithelium of patients with active celiac disease and refractory celiac sprue. IL-15 was not secreted but delivered at the surface of enterocytes. IL-15 specifically induced the expansion and survival of the clonal abnormal intraepithelial lymphocytes that characterize refractory celiac sprue and triggered their secretion of interferon gamma and their cytotoxicity against intestinal epithelial cells. Comparable activating signals could be delivered by IL-15 expressed at the membrane of the T84 enterocyte cell line. CONCLUSIONS: These data provide strong evidence that uncontrolled overexpression of IL-15 in refractory celiac sprue perpetuates epithelial damage and promotes the emergence of T-cell clonal proliferations. Blocking IL-15 might prove useful to treat this severe complication of celiac disease.

Adult↗
PubMed2003

Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells.

BACKGROUND: During continuous ambulatory peritoneal dialysis, the peritoneum is exposed to bioincompatible dialysis fluids that cause denudation of mesothelial cells and, ultimately, tissue fibrosis and failure of ultrafiltration. However, the mechanism of this process has yet to be elucidated. METHODS: Mesothelial cells isolated from effluents in dialysis fluid from patients undergoing continuous ambulatory peritoneal dialysis were phenotypically characterized by flow cytometry, confocal immunofluorescence, Western blotting, and reverse-transcriptase polymerase chain reaction. These cells were compared with mesothelial cells from omentum and treated with various stimuli in vitro to mimic the transdifferentiation observed during continuous ambulatory peritoneal dialysis. Results were confirmed in vivo by immunohistochemical analysis performed on peritoneal-biopsy specimens. RESULTS: Soon after dialysis is initiated, peritoneal mesothelial cells undergo a transition from an epithelial phenotype to a mesenchymal phenotype with a progressive loss of epithelial morphology and a decrease in the expression of cytokeratins and E-cadherin through an induction of the transcriptional repressor snail. Mesothelial cells also acquire a migratory phenotype with the up-regulation of expression of alpha2 integrin. In vitro analyses point to wound repair and profibrotic and inflammatory cytokines as factors that initiate mesothelial transdifferentiation. Immunohistochemical studies of peritoneal-biopsy specimens from patients undergoing continuous ambulatory peritoneal dialysis demonstrate the expression of the mesothelial markers intercellular adhesion molecule 1 and cytokeratins in fibroblast-like cells entrapped in the stroma, suggesting that these cells stemmed from local conversion of mesothelial cells. CONCLUSIONS: Our results suggest that mesothelial cells have an active role in the structural and functional alteration of the peritoneum during peritoneal dialysis. The findings suggest potential targets for the design of new dialysis solutions and markers for the monitoring of patients.

Cell Movement↗
PubMed2005

Tandem Sp1/Sp3 sites together with an Ets-1 site cooperate to mediate alpha11 integrin chain expression in mesenchymal cells.

Alpha11beta1 integrin is a collagen receptor, which is expressed in a highly regulated manner in a specific subset of ectomesenchymally and mesodermally derived cells. We previously established that a 3 kb region upstream of the transcription start site of the ITGA11 gene efficiently induced alpha11 transcription in a cell-type specific manner. Using the human fibrosarcoma cell line HT1080 and human skin fibroblasts, we now report that the majority of the activity in the proximal promoter resides in a region spanning nt +25 to nt -176. Mutation and deletion analyses using luciferase reporter assays showed that tandem low affinity Sp1/Sp3 binding sites, together with an Ets-1-like binding site, were needed for the proximal promoter activity in mesenchymal cells. EMSAs and supershift assays showed that Sp1 and Sp3 both bind to the Sp1/Sp3 binding sites, whereas occupation of the Ets-1 binding site appears to be Sp3-dependent. Chromatin immunoprecipitation assays verified that Sp1, Sp3 and Ets-1 can bind the promoter in vivo. In heterologous Drosophila SL2 cells, Sp1, Sp3 and Ets-1 all transactivated the alpha11 promoter, with Sp1 being the most efficient activator. The lack of any synergistic effect of Sp1/Sp3 and Ets-1 in SL2 cells indicates that an Ets family member other than Ets-1 might be involved in regulating alpha11 transcription in mesenchymal cells. The central role of Sp1 in regulating alpha11 RNA transcription was further verified by the ability of the Sp1 inhibitor mithramycin A to efficiently attenuate alpha11 RNA and protein levels in primary fibroblasts. The proximal promoter itself was able to confer cell-type specific transcription on HT1080 cells and embryonic fibroblasts but not on U2OS and JAR cells. We speculate that the "mesenchymal signature" of alpha11 integrin gene expression is controlled by the activity of Sp1/Sp3, fibroblast-specific combinations of Ets family members and yet unidentified enhancer-binding transcription factors.

Animals↗
PubMed2003

Glomerular and renal vascular structural changes in alpha8 integrin-deficient mice.

Integrins are matrix receptors that regulate cell-matrix interactions during development and in adult tissue. In the adult kidney, the alpha8 chain is specifically expressed in glomerular mesangial cells and vascular smooth muscle cells. alpha8-deficient (alpha8-/-) mice demonstrate reductions in renal mass, which can range from complete renal agenesis to the development of kidneys that are only slightly smaller than wild-type kidneys. No histologic abnormalities of these kidneys have been described. However, considering the prominent expression of alpha8 in glomeruli and renal vessels, it seemed unlikely that the kidneys of alpha8-/- mice would be completely normal. Therefore, the renal phenotype of adult alpha8-/- mice was investigated, for assessment of more subtle morphologic alterations in kidney tissue. alpha8-/- mice displayed a significant reduction in nephron number and an increase in glomerular volume, compared with wild-type control animals. Albuminuria was not different in wild-type and alpha8-/- mice. Quantitative morphologic analyses revealed that the glomeruli of alpha8-/- mice were hypercellular, with an increased number of mesangial cells, compared with wild-type mice. Mesangial matrix deposition (as demonstrated for collagen IV and the alpha8 ligand fibronectin) was expanded in alpha8-/- mice, compared with wild-type mice. Collagens I and III, which are not normally present in glomeruli, were detected in the glomeruli of alpha8-/- mice. Staining for other glomerular integrins demonstrated an increased abundance of the collagen receptor alpha2 integrin in alpha8-/- mice. The glomerular capillary length density was significantly greater in alpha8-/- mice than in wild-type mice. Cortical arterial vessel walls were not altered in alpha8-/- mice, but the capillaries of the peritubular network were widened. Despite the strong mesangial and vascular expression of alpha8, glomerular and renal vascular alterations in alpha8-/- mice were relatively mild. Only aged alpha8-/- mice demonstrated increased glomerular capillary widening, compared with control animals. The results suggest that the lack of alpha8 can be largely compensated for, at least in younger alpha8-/- mice. It is not yet clear whether the occurrence of collagens that are not normally present in glomeruli and the increased abundance of the collagen receptor alpha2 contribute to maintaining the glomerular structure in alpha8-/- mice. The compensatory mechanisms involved will be the subject of future research.

Animals↗
PubMed1999

Chloramphenicol-induced mitochondrial dysfunction is associated with decreased transferrin receptor expression and ferritin synthesis in K562 cells and is unrelated to IRE-IRP interactions.

Chloramphenicol is an antibiotic that consistently suppresses the bone marrow and induces sideroblastic anemia. It is also a rare cause of aplastic anemia. These toxicities are thought to be related to mitochondrial dysfunction, since chloramphenicol inhibits mitochondrial protein synthesis. We hypothesized that chloramphenicol-induced mitochondrial impairment alters the synthesis of ferritin and the transferrin receptor. After treating K562 erythroleukemia cells with a therapeutic dose of chloramphenicol (10 microg/ml) for 4 days, there was a marked decrease in cell surface transferrin receptor expression and de novo ferritin synthesis associated with significant decreases in cytochrome c oxidase activity, ATP levels, respiratory activity, and cell growth. Decreases in the transferrin receptor and ferritin were associated with reduced and unchanged message levels, respectively. The mechanism by which mitochondrial dysfunction alters these important proteins in iron homeostasis is not clear. A global decrease in synthetic processes seems unlikely, since the expression of the cellular adhesion proteins VLA4 and CD58 was not significantly decreased by chloramphenicol, nor were the message levels of beta-actin or ferritin. The alterations were not accompanied by changes in binding of the iron response protein (IRP) to the iron-responsive element (IRE), although cytosolic aconitase activity was reduced by 27% in chloramphenicol-treated cells. A disturbance in iron homeostasis due to alterations in the transferrin receptor and ferritin may explain the hypochromic-microcytic anemia and the accumulation of nonferritin iron in the mitochondria in some individuals after chloramphenicol therapy. Also, these studies provide evidence of a link between mitochondrial impairment and iron metabolism in K562 cells.

Aconitate Hydratase↗
PubMed1998

Up-regulation of alphaEbeta7, a novel integrin adhesion molecule, on T cells from systemic lupus erythematosus patients with specific epithelial involvement.

OBJECTIVE: To determine the possible role of a novel integrin, alphaEbeta7, in the pathogenesis of systemic lupus erythematosus (SLE). METHODS: Expression of alphaEbeta7 was examined on peripheral blood lymphocytes (PBL) from normal subjects (n = 25) and patients with SLE (n = 31), primary Sjogren's syndrome (n = 7), or polymyositis/dermatomyositis (n = 8) by cytofluorometry and/or immunoprecipitation. Adhesion of alphaEbeta7+ T cells to HSG epithelial cells was investigated using a confocal image analyzer. RESULTS: After phytohemagglutinin stimulation, expression of alphaEbeta7 on PBL, especially on CD8+ T cells, was significantly higher in SLE patients than in normal subjects (P<0.01). Elevated alphaEbeta7 expression was associated with the presence of oral ulcers or serositis (P<0.05). Activated SLE T cells with enhanced alphaEbeta7 expression strongly adhered to HSG; this adhesion was partially blocked by anti-alphaEbeta7. CONCLUSION: Expression and adhesion of alphaEbeta7 on activated PBL was significantly increased in patients with SLE with epithelial involvement. This suggests a role of this novel integrin in tissue-specific retention of activated PBL, due to increased alphaEbeta7-E-cadherin interaction, which may contribute to epithelial inflammation.

Adult↗
PubMed2004

Development of a mammalian series-fibered muscle.

This study examines the processes by which multiply innervated, serially fibered mammalian muscles are constructed during development. We previously reported that primary myotubes of such a muscle, the guinea pig sternomastoid muscle, span from tendon to tendon and are innervated at each of the muscle's four innervation zones. Secondary myotubes form later, in association with each point of innervation (Duxson and Sheard, Dev. Dyn., 1995; 204:391-405). We now describe the further growth and development of the muscle. Secondary myotubes initially insert onto and grow along the primary myotube. However, as they reach a critical length, they encounter other secondary myotubes growing from serially adjacent innervation zones and may transfer their attachment(s) to these serially positioned secondary myotubes. Other secondary myotubes maintain attachment at one or both ends to their primary myotube. Thus, an interconnected network of primary and secondary myotubes is formed. Patterns of reactivity for cell adhesion molecules suggest that early attachment points between myotubes are the embryonic precursors of adult myomyonal junctions, characterized by the expression of alpha7Bbeta1 integrin. Finally, the results show that secondary myotubes positioned near a tendon are generally longer than those lying in the mid belly of the muscle, and we suggest that the environment surrounding the tendinous zone may somehow stimulate myotube growth.

Aging↗
PubMed2006

Thymosin beta10 inhibits cell migration and capillary-like tube formation of human coronary artery endothelial cells.

Thymosin beta10 is a cytoplasm G-actin sequestering protein whose functions are largely unknown. To determine the direct effects of exogenous thymosin beta10 on angiogenic potentials as endothelial cell migration and capillary-like tube formation, human coronary artery endothelial cells (HCAECs) were incubated with increasing doses of thymosin beta10 (25-100 ng/ml). By using a modified Boyden chamber assay, thymosin beta10 inhibited cell migration in a dose- and time-dependent manner with the maximal effect being a 36% reduction at 100 ng/ml as compared to controls (P < 0.01). In addition, thymosin beta10 (100 ng/ml) significantly inhibited the capillary-like tube-formation of HCAECs on Matrigel, showing a 21% reduction of the total tube length as compared to negative controls (P < 0.01). Furthermore, by using real time PCR analysis, thymosin beta10 significantly decreased mRNA levels of vascular endothelial growth factor (VEGF), VEGF receptor-1 (VEGFR-1) and integrin alphaV after 24 h treatment in HCAECs. By contrast, thymosin beta4 significantly increased HCAEC migration. These results indicate that thymosin beta10, but not thymosin beta4, have direct inhibitive effects on endothelial migration and tube formation that might be mediated via downregulation of VEGF, VEGFR-1 and integrin alphaV in HCAECs. This study suggests a potential therapeutic application of thymosin beta10 to the diseases with excessive angiogenesis such as cancer.

Capillaries↗
PubMed2004

Expression of syndecan-1 and expression of epidermal growth factor receptor are associated with survival in patients with nonsmall cell lung carcinoma.

BACKGROUND: Recently, the authors identified molecular signatures and pathways associated with nonsmall cell lung carcinoma histology and lung development. They hypothesized that genetic classifiers of histology would provide insight into lung tumorigenesis and would be associated with clinical outcome when evaluated in a broader set of specimens. METHODS: Associations between patient survival and immunostaining for 11 representative histologic classifiers (epidermal growth factor receptor [EGFR], CDK4, syndecan-1, singed-like, TTF-1, keratin 5, HDAC2, docking protein 1, integrin alpha3, P63, and cyclin D1) were examined using a tissue microarray constructed from nonsmall cell lung carcinoma specimens. RESULTS: Sixty-three tumors were examined, including 43 adenocarcinomas, 11 large cell carcinomas, and 9 squamous cell carcinomas. Sixty-three percent of tumors were clinical Stage I lesions, and 37% were Stage II-III lesions. In a multivariate analysis that controlled for age, gender, and race, syndecan-1 expression was found to be associated with a significant reduction in the risk of death (hazard ratio, 0.31 [95% confidence interval, 0.18-0.87]; P < 0.05). Multivariate analysis also indicated that EGFR expression was associated with a significant reduced risk of death. CONCLUSIONS: The authors demonstrated that expression of either of the nonsmall cell lung carcinoma subtype classifiers syndecan-1 and EGFR was associated with a 30% reduction in the risk of death, with this reduction being independent of histology and other confounders. The results of the current study suggest that loss of expression of these histologic classifiers is associated with biologic aggressiveness in lung tumors and with poor outcome for patients with such tumors. If their significance can be validated prospectively, these biomarkers may be used to guide therapeutic planning for patients with nonsmall cell lung carcinoma.

Adenocarcinoma↗
PubMed2007

HIV-1-infected children on HAART: immunologic features of three different levels of viral suppression.

BACKGROUND: HIV-1-infected children show changes of blood lymphocyte subpopulations. We have, therefore, investigated how highly active anti-retroviral therapy (ART) alter these subsets. Blood samples were taken from 41 HIV-1-infected children on ART who were divided into groups showing good, partial and poor responses to ART on the basis of viral load (VL) measurement in blood. The observations were compared to those seen in 20 uninfected children. METHODS: The samples were studied using 4-color flow cytometry for "naïve", central memory and effector memory cells as well as for CD38 expression as the sign of activation within both the CD4+ and the CD8+ T cell populations. HIV-1 infected children were also evaluated for the presence and the titers of antibodies induced by vaccination against childhood infections in our patients while on HAART. RESULTS: Lymphocyte counts were lower in the "poor" viral load responding (VLR) group when compared with partial and good VLRs. Poor VLRs had lower total and naïve CD4+ T cell counts. HIV-1-infected children from all three groups had high CD8+ T cell counts. Central memory CD4+ and CD8+ T cell percentages were particularly low in the poor VLR group while in the poor VLR group the percentages of effector memory CD4+ and CD8+ T cells were higher when compared with the control group. Higher cellular activation of CD8+ T cells was observed in HIV-1-infected children, particularly when analyzed for the intensity of CD38 expression in the poor VLR group. CD5 expression on B cells was higher among all HIV-1-infected children. Antibodies to tetanus, diphtheria, measles, rubella, and hepatitis B were present in a large proportion of children but the titers were similarly low for all three groups of HIV-infected children. CONCLUSIONS: Children with different levels of viral response to HAART present immune phenotype characteristics that tend to place the children with partial and good virological responses into the same group. These children are still moderately deficient in their immune responses but show better recovery than seen with children in the poor VLR group. These observations indicate that the proportions of central memory cells among the CD4+ T cells and the intensity of the expression of CD38 activation antigen on CD8+ T cells provide more informative parameters for monitoring children on HAART than the absolute numbers of CD4+ and CD8+ T cells alone.

AIDS Vaccines↗
PubMed2004

Regional distribution of alpha9beta1 integrin within the limbus of the mouse ocular surface.

The epithelial basal cells of the corneal limbus are known to contain adult corneal epithelial stem cells, but the properties of these cells are not well understood. In addition, how and when the limbal epithelium forms during postnatal development in mammals is not clear. To better understand the anatomy and cell biology of the limbus, a whole-mount procedure was used to show that the nasal, inferior, temporal, and superior regions of the mouse limbus contain different numbers of alpha9 integrin-positive cells most of which are observed in the nasal region. We also show that this pattern develops progressively over time from 1 to 8 weeks after birth. High magnification image projections and three-dimensional reconstructions of the limbal region were generated from confocal images obtained after tissues were dual stained with alpha9 integrin and propidium iodide (PI) or triple stained with alpha9 integrin, E-cadherin, and PI. Data show that alpha9 integrin is present on the adult mouse cornea in the limbal basal cells and is more abundant in the apical-most cytoplasm of the limbal basal cells, where it can be found colocalized within the plasma membrane with E-cadherin. These studies are an important step toward improving our understanding of the development and cell biology of limbal basal cells.

Aging↗
PubMed1992

Mapping of the human VLA-alpha 4 gene to chromosome 2q31-q32.

The integrin VLA-4 (alpha 4: beta 1; CD49d/CD29) is involved in both cellular adhesion to extracellular matrix and cell-cell interactions. We have determined that the human gene coding for VLA-alpha 4 is located on the long arm of chromosome 2 by using fluorescence in situ hybridization. The VLA-alpha 4 gene has been more precisely mapped to the 2q31-q32 region after GTG banding (G-bands by trypsin using Giemsa). These data suggest that the VLA-4 gene belongs to the COL3A1-(ELN-FN)-COL6A3 linkage group and establishes a potential genetic relationship between the alpha 4 and alpha v integrin subunits.

Cell Adhesion↗
PubMed1995

Transforming growth factor-beta 1-induced expression of the mucosa-related integrin alpha E on lymphocytes is not associated with mucosa-specific homing.

The integrin alpha E (HML-1, alpha IEL, alpha M290) is largely expressed on lymphocytes in epithelial sites, especially the gut mucosa. We investigated whether alpha E has any role in homing or delineates a phenotype with distinct migratory behavior. Lymph node T cells were stimulated for 5 days with anti-CD3 in the presence or absence of transforming growth factor (TGF)-beta 1 to generate alpha E+ or alpha E- cells, respectively. The two populations were then tested for their homing properties in mice. Both alpha E+ (TGF-beta-treated) and alpha E- (control) cells of either CD4+ or CD8+ subset had a low capacity to enter the gut and showed the same homing behavior with respect to a variety of other organs. The same was true for alpha E+ and alpha E- cells that had been briefly stimulated with anti-CD3 (24 h) and then allowed to return to a resting state before injection, though in this case both populations showed a greater capacity to recirculate through lymphoid tissue than was seen with fully activated cells. The results indicate that alpha E beta 7 does not act as a homing receptor, and that the expression of the site-specific marker alpha E does not correlate with a distinct homing behavior.

Animals↗
PubMed1997

In vivo rolling and endothelial selectin binding of mononuclear leukocytes is distinct from that of polymorphonuclear cells.

In inflammation, rolling of leukocytes along the microvascular endothelium is a precondition for subsequent integrin-mediated firm adhesion and extravasation. Rolling characteristics of polymorphonuclear leukocytes (PMNL) and mononuclear leukocytes (MNL) in small venules (15-25 microns) of the rat mesentery were studied by intravital fluorescence microscopy under basal conditions and after intravenous treatment with an anti-rat neutrophil serum (ANS). The baseline rolling fraction of the venular total leukocyte flux was 36 +/- 15% (mean +/- SD). The PMNL fraction of the systemic leukocyte count was 27 +/- 9%. Treatment with ANS resulted in total depletion of circulating PMNL and reduced the leukocyte rolling fraction to 12 +/- 5%, in this situation represented only by MNL. In rats treated intraperitoneally with interleukin (IL)-1 beta for 4 h, the leukocyte rolling fraction was 53 +/- 13% and was reduced to 33 +/- 11% after ANS treatment. These data indicated that most, if not all, circulating PMNL rolled along the venular endothelial lining in the rat mesentery prepared for intravital microscopy, whereas MNL rolling was minor (approximately 10%) under the same basal condition. In cytokine-activated tissue, on the other hand, the number of rolling MNL was greatly increased. While PMNL rolling is known to be entirely selectin dependent, the increased MNL rolling after IL-1 stimulation was likely mediated by alpha 4 integrins, inasmuch as the rolling fraction of isolated peripheral blood lymphocytes injected into the microcirculation of the cytokine-stimulated mesentery was reduced from 31 +/- 14% to 6 +/- 2% by pretreatment of the cells with a monoclonal antibody against the rat integrin alpha 4 chain. In accordance with the in vivo rolling characteristics of the two cell populations, binding of soluble P- or E-selectin (selectin/IgG chimeras) was less intense for blood lymphocytes than for granulocytes, as determined by flow cytometric analyses of rat and human leukocytes. Taken together, our findings in vivo indicate that the adhesive interactions responsible for rolling of PMNL and MNL, respectively, are distinct in terms of receptor occupancy, and may help explain the temporal selectivity in recruitment of different leukocyte subpopulations in inflammatory or immune reactions.

Animals↗
PubMed2003

Selective absence of CD8+ TCRalpha beta+ intestinal epithelial cells in transgenic mice expressing beta2-microglobulin-associated ligands exclusively on thymic cortical epithelium.

Whereas interactions between the TCRalpha beta and self MHC:peptide complexes are clearly required for positive selection of mature CD4(+) and CD8(+) T cells during intrathymic development, the role of self or foreign ligands in maintaining the peripheral T cell repertoire is still controversial. In this report we have utilized keratin 14-beta2-microglobulin (K14-beta2m)-transgenic mice expressing beta2m-associated ligands exclusively on thymic cortical epithelial cells to address the possible influence of TCR:ligand interactions in peripheral CD8(+) T cell homeostasis. Our data indicate that CD8(+) T cells in peripheral lymphoid tissues are present in normal numbers in the absence of self MHC class I:peptide ligands. Surprisingly, however, steady state homeostasis of CD8(+) T cells in the intestinal epithelium is severely affected by the absence of beta2m-associated ligands. Indeed TCRalpha beta(+) IEL subsets expressing CD8alpha beta or CD8alpha alpha are both dramatically reduced in K14-beta2m mice, suggesting that the development, survival or expansion of CD8(+) IEL depends upon interaction of the TCR with MHC class I:peptide or other beta2m-associated ligands elsewhere than on thymic cortical epithelium. Collectively, our data reveal an unexpected difference in the regulation of CD8(+) T cell homeostasis by beta2m-associated ligands in the intestine as compared to peripheral lymphoid organs.

Animals↗
PubMed2003

Aging-dependent generation of suppressive CD4+CD25-R123loCD103+ T cells in mice.

Advancing age is associated with significant alterations in immune functions, including a decline in CD4 T cell function, in both mice and humans. In our previous report, we showed that CD4(+)CD25(-) T cells in aged (24-month-old) mice, especially after in vitro pre-stimulation of these cells, exhibit hyporesponsive and suppressive properties. We examined here whether the suppressive activity of aged CD4(+)CD25(-) T cells is ascribable to a particular population within these cells. In vitro analyses revealed that cell populations rapidly extruding Rhodamine-123 (R123) (referred to as R123(lo) cells) in aged CD4(+)CD25(-) T cells have a more potent suppressive function compared with R123(hi) populations. In addition, CD103(+) cells in freshly prepared aged CD4(+)CD25(-)R123(lo) T cells had a most potent suppressive activity. Both R123(hi) and R123(lo) populations had individually stronger suppressive activity after pre-stimulation than before pre-stimulation. Furthermore, the R123(lo) population in young CD4(+)CD25(-) T cells also had different properties from R123(hi) T cells: low responsiveness, no additive effect in proliferation assays, and the gain of a suppressive function after in vitro pre-stimulation. Taken together, these results suggest that CD4(+)CD25(-)R123(lo) T cells are a unique population within whole CD4(+)CD25(-) T cells. This population exists in the early stage of the life span, and the properties in this population become obvious with aging, that is the gain of their suppressive activity.

Aging↗