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CD27, a lymphocyte-specific member of the TNF/NGF-R family, is expressed on the majority of peripheral blood T cells. Activation of T cells via TCR/CD3 induces high CD27 surface expression and the release of a soluble extracellular part of the molecule. After prolonged activation in vitro, CD27 becomes gradually switched off. There is evidence that also in vivo, CD4+ cells that have persistently been stimulated by Ag, accumulate within the CD45RA-CD27- subset. In addition, an increase of CD27- T cells has been observed under certain immunopathologic conditions and during aging. This study was undertaken to analyze the regulation of CD27 on different T-cell subsets and to determine whether the loss of CD27 expression is an irreversible event and may thereby mark T-cell differentiation. In agreement with earlier findings, all CD4+CD45RA+CD45RO- T cells were found to express CD27, whereas a small fraction of the CD4+CD45RA-CD45RO+ subset lacks the molecule. In contrast, within the CD8+ compartment CD27- subsets were found both in the CD45RA+ and CD45RA- subpopulations. After stimulation with CD3 mAb, both CD27 membrane expression and release was equally up-regulated in CD4+ and CD8+ subpopulations. This stimulus, however, provoked a strikingly predominant up-regulation of membrane CD27 on CD45RO- cells as compared with CD45RA- cells. On CD4+CD45RA-CD27- T cells and long-term grown CD45RA-CD27- TLC, CD27 expression could not be reinduced after stimulation of the TCR/CD3 complex, neither at the protein nor at the mRNA level. Comparison of CD27 expression with its structural homologue FAS/APO-1 showed that down-regulation after prolonged activation is not a general feature of TNF/NGF-R family members. The CD27 ligand was recently identified and was shown to give a co-stimulatory signal to PHA-activated T cells. The restricted up-regulation of CD27 on CD45RA+ cells after T-cell stimulation may point at a discrete role of CD27-CD27 ligand interaction during transition of CD45RO- to CD45RA- T cells. In addition, the CD27 negative phenotype seems a stable reflection of differentiation rather than of activation.

We have characterized the activation state of T cells in the bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) from patients with sarcoidosis, to obtain more information about their mechanisms of activation. We analyzed the expression of activation markers (CD25, HLA-DR, Leu-8, and two recently defined markers, CD69 and CD27) on T cells by two-color flow cytometry. We also measured the levels of soluble CD27 and soluble CD25 in nonconcentrated BALF and in serum by ELISA. We found that most T cells in BALF from patients, but not in the peripheral blood, expressed CD69, whereas they did not express CD27. The phenotype (CD69+CD27-) of most BALF T cells and the coexpression of CD69 with HLA-DR and/or VLA-1 indicates that they are in a state of recent and persistent activation. We confirmed previous findings of expression of CD25, HLA-DR, and Leu-8 by T lymphocytes in BALF from patients. We also confirmed increased levels of soluble CD25 in the serum from these patients. The levels of sCD27 and sCD25 in the epithelial lining fluid (ELF) were calculated on the basis of urea in BALF and serum. They were increased in the patients compared with control subjects. In both patients and control subjects, levels in ELF were higher than in the peripheral blood. This indicates shedding of sCD27 (and sCD25) in the lung compartment, which likely contributes to levels in the serum. It is known that in vitro CD27+ cells become CD27- after repeated stimulation and that CD27- cells, after restimulation, do not shed sCD27.(ABSTRACT TRUNCATED AT 250 WORDS)

The human T cell Ag CD27 belongs to a recently defined family of cell surface receptors, including the nerve growth factor receptor, two distinct tumor necrosis factor receptors, and the B cell specific molecule CD40. On resting T cells, CD27 is a transmembrane homodimer with subunits of 50 to 55 kDa (p55). T cell activation via the TCR/CD3 complex causes a strong enhancement of p55 expression. Concomitantly, an alternative form of the CD27 molecule with a molecular mass of 28 to 32 kDa (p32) appears at the cell surface. With the use of ELISA, we here show that a soluble form of CD27 (sCD27) can be detected in the supernatant of T cells activated with anti-CD3 or combinations of anti-CD2 mAb. Moreover, sCD27 is found in both serum and urine from healthy donors. sCD27, purified from either culture supernatant or urine, has a molecular mass of 28 to 32 kDa and is, according to peptide mapping, structurally homologous to the p55 membrane form of CD27. Quantification of sCD27 levels may be used as a marker for T lymphocyte activation in vivo.

Objectives - Recently, effector T-cell subpopulations have been identified that can be distinguished by expression of members of the TNF-R family: CD4 + OX-40 + cells are CD4 helper-effector cells CD8 + CD45RA + CD27 cells are CD8-killer-effector cells. We investigated whether these lymphocyte subsets were increased in the active phase of multiple sclerosis (MS). Material and methods - Multiple colour immunofluorescence staining was performed on peripheral blood lymphocytes of 28 patients with active MS and of 29 healthy controls, followed by FACS analysis. Results - Frequencies of CD8-killer-effector cells showed a wide interindividual range in both groups and percentages of CD4 helper-effector cells were low. No significant difference between the groups was observed for these subsets, but CD8 + CD45RA CD27 were increased in MS. In healthy individuals, CD4 helper-effector cells correlated with the total percentages of memory cells. Moreover, CD4 + and CD8 + memory cells were strongly correlated. Conclusions - The here described recently identified effector CD4 and CD8 lymphocyte subpopulations were not increased in clinically active MS. It is however still possible that in MS, myelin-specific encephalitogenic cells reside within these subsets.

Genome-wide association studies involve several hundred thousand markers and, even when quality control is scrupulous, are invariably confounded by residual uncorrected errors that can falsely inflate the apparent difference between cases and controls (so-called genomic inflation). As a consequence such studies inevitably generate false positives alongside genuine associations. By use of Bayesian logic and empirical data, the Wellcome Trust Case Control Consortium suggested that association studies in complex disease should involve at least 2000 cases and 2000 controls, at which level they predicted that p values of less than 5×10 −7 would more commonly signify true positives than false positives.

CD27, a transmembrane disulfide-linked 55-kD homodimer, belongs to the nerve growth factor-receptor family, a group of homologous molecules involved in lymphocyte differentiation and selection. It is expressed on mature thymocytes, peripheral blood T cells, and a subpopulation of B cells. We investigated the expression of CD27 on malignant B cells representative for a broad range of stages in physiologic antigen- independent and -dependent B-cell development. In normal lymphoid tissue CD27+ B cells were only found in the peripheral blood (29.8% +/- 10.8%, n = 13) and in germinal centers. With the exception of pro-B and the majority of pre-pre-B acute lymphocytic leukemias and of myelomas, CD27 expression of variable intensity was detected on almost all immature and mature malignant B cells tested. Moreover, using a sandwich enzyme-linked immunosorbent assay we could show the presence of sometimes very high (up to 6,000 U/mL; normal values < 190 U/mL) amounts of the soluble 28- to 32-kD form of CD27 (sCD27) in the sera of patients with B-cell malignancies. The highest levels of sCD27 were observed in patients with chronic lymphocytic leukemia and low-grade non-Hodgkin's lymphomas. Most importantly, both in transversal and longitudinal studies, we found a strong correlation between sCD27 levels in the serum and tumor load, indicating that sCD27 can be used as a disease-marker in patients with acute and chronic B-cell malignancies.

The recently identified CD27 ligand (L) is a type II transmembrane molecule with significant structural homology to tumor necrosis factor (TNF)-alpha, TNF-beta, lymphotoxin beta, CD40L, and CD30L. Using a CD27L specific mAb we examined the tissue distribution of the molecule, and found its expression to be restricted to B cells in occasional germinal centers, stromal cells in the thymic medulla, and scattered T cells in tonsils, skin and gut. As the limited expression of CD27L closely resembled the reported distribution of the activation antigen CD70, we tested whether CD70 represents the human CD27L. CD70 mAb were found to react with CD27L-expressing transfected mouse fibroblasts. Moreover a number of CD70 mAb could specifically interfere with the cellular binding of CD27L mAb. Thus, CD70 is identical to the human CD27L.