Control of lymphocyte function through CD27–CD70 interactions

In contrast to the expression of other TNFR/TNF family members, expression of CD27 and its ligand CD70 is predominantly confined to lymphocytes. High expression levels of CD27 appear to be dependent on proper ligation of antigen receptors, whereas for the induction of CD70 expression additional (co–stimulatory and/or pro–inflammatory) signals are required. Next to membrane–bound CD27 also a soluble form of CD27 is produced in the course of the immune response. Soluble CD27 (sCD27) is found in body fluids and can be used to monitor local and systemic immune activation. In addition, elevated serum concentrations of sCD27 are found in patients with B cell malignancies and levels of sCD27 strongly correlate with tumor load. Based on functional experiments andin vitroexpression regulation data, we propose that interactions between activated lymphocytesin vivocan result in CD27–CD70 interactions that may regulate the size and function of antigen–primed lymphocyte populations.     

CD27 and CD70 in T cell and B cell activation

In vitro work has defined the TNF receptor family member CD27 as a T and B cell co-stimulatory molecule. Its activity is governed by the transient availability of its TNF-like ligand CD70 on lymphocytes and dendritic cells. Recent studies, enforcing or abrogating CD27 function by genetic or protein intervention in mouse models have revealed key contributions of the CD27-CD70 system to effector and memory T cell formation, which is probably based on improved cell survival. The stimulatory effects of CD27 on B cell function appear to oppose those of CD70, which also has a signaling role. Targeting CD27-CD70 for therapy is attractive but should take into account the fact that constitutive CD27 stimulation culminates in lethal immunodeficiency.     

CD27/CD70 interactions regulate T dependent B cell differentiation

CD27 is a tumor necrosis factor (TNF) receptor family member whose expression is limited to cells of the lymphoid lineage. Constitutively expressed on T lymphocytes, it is a constimulatory molecule for a regulatory subset. Induced on B lymphocytes after antigenic challenge, it is a marker of memory cells. CD70, CD27 ligand, is a TNF related trans-membrane protein induced upon activation on T and B cells. In complement of ligation of CD40, another TNF receptor family member expressed by B cells CD27/CD70 interaction plays a key role in T dependent B cell responses and is responsible for plasma cell differentiation. B lymphocyte responses appear thus controlled by different T cell subsets expressing CD 154 (CD40 ligand), CD27, or CD70 (CD27 ligand).     

Synergistic augmentative effect of interleukin-10 and CD27/CD70 interactions on B-cell immunoglobulin synthesis.

Interleukin-10 (IL-10) is a potent cytokine that regulates immunoglobulin synthesis by B cells. CD27/CD70 interactions by direct cell-to-cell contact are also needed to produce substantial amounts of immunoglobulin. We have investigated the effects of IL-10 and CD27/CD70 interactions on the immunoglobulin synthesis. In the presence of IL-10 stimulation, the production of IgG, IgM and IgA was increased synergistically by the addition of CD27 ligand (CD70)-transfectants in a dose-dependent manner, which was completely blocked by anti-CD70 monoclonal antibody. In contrast, CD70-transfectants additively enhanced the immunoglobulin production in the presence of IL-2, IL-4, or IL-6. The synergistic enhancement of the immunoglobulin production by IL-10 and CD70-transfectants was remarkable in highly purified CD27+ B cells, but there was no immunoglobulin production in CD27- B cells. Furthermore, by the addition of CD70-transfectants, the synthesis of IgG1, IgG2, IgG3 and IgG4 was also enhanced in the presence of IL-10. On the other hand, IL-10 diminished CD27 expression in B cells. B-cell proliferation was augmented by CD70-transfectants with IL-10 or IL-10 plus IL-2. The addition of IL-2 further augmented the immunoglobulin production which was synergistically enhanced by IL-10 and CD27 triggering. Taken together, the co-operative response to IL-10 and CD27/CD70 interactions regulates B-cell immunoglobulin production.     

p27Kip1 modulates cell migration through the regulation of RhoA activation

The tumor suppressor p27(Kip1) is an inhibitor of cyclin/cyclin-dependent kinase (CDK) complexes and plays a crucial role in cell cycle regulation. However, p27(Kip1) also has cell cycle-independent functions. Indeed, we find that p27(Kip1) regulates cell migration, as p27(Kip1)-null fibroblasts exhibit a dramatic decrease in motility compared with wild-type cells. The regulation of motility by p27(Kip1) is independent of its cell-cycle regulatory functions, as re-expression of both wild-type p27(Kip1) and a mutant p27(Kip1) (p27CK(-)) that cannot bind to cyclins and CDKs rescues migration of p27(-/-) cells. p27(-/-) cells have increased numbers of actin stress fibers and focal adhesions. This is reminiscent of cells in which the Rho pathway is activated. Indeed, active RhoA levels were increased in cells lacking p27(Kip1). Moreover, inhibition of ROCK, a downstream effector of Rho, was able to rescue the migration defect of p27(-/-) cells in response to growth factors. Finally, we found that p27(Kip1) binds to RhoA, thereby inhibiting RhoA activation by interfering with the interaction between RhoA and its activators, the guanine-nucleotide exchange factors (GEFs). Together, the data suggest a novel role for p27(Kip1) in regulating cell migration via modulation of the Rho pathway.     

Lethal T cell immunodeficiency induced by chronic costimulation via CD27-CD70 interactions

It has been proposed that HIV-1, in addition to directly infecting and killing CD4+ T cells, causes T cell dysfunction and T cell loss by chronic immune activation. We analyzed the effects of chronic immune activation in mice that constitutively expressed CD70, the ligand for the tumor necrosis factor receptor family member CD27, on B cells. CD70 transgenic (CD70 Tg) mice showed a progressive conversion of naive T cells into effector-memory cells, which culminated in the depletion of naive T cells from lymph nodes and spleen. T cell changes depended on continuous CD27-CD70 interactions and T cell antigen receptor stimulation. Despite this hyperactive immune system, CD70 Tg mice died aged 6-8 months from Pneumocystis carinii infection, a hallmark of T cell immunodeficiency. Thus, persistent delivery of costimulatory signals via CD27-CD70 interactions, as may occur during chronic active viral infections, can exhaust the T cell pool and is sufficient to induce lethal immunodeficiency.     

CD27/CD70 pathway activation in primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder

Primary cutaneous CD4+ small or medium T-cell lymphoproliferative disorder (PCSM-LPD) is a clonal T-cell proliferation disease confined to the skin. PCSM-LPD shares expression of T follicular helper (Tfh) cell markers with various mature T-cell lymphomas. However, the benign presentation of PCSM-LPD contrasts the clinical behavior of other Tfh-lymphomas. The aim of our study was to delineate the molecular similarities and differences between PCSM-LPD and other Tfh-derived lymphomas to explain the clinical behavior and unravel possible pathological mechanisms. We performed targeted next-generation sequencing of 19 genes recurrently mutated in T-cell neoplasms in n = 17 PCSM-LPD with high and in n = 21 PCSM-LPD with low tumor cell content. Furthermore, gene expression profiling was used to identify genes potentially expressed in the PD1-positive (PD1+) neoplastic cells. Expression of some of these genes was confirmed in situ using multistain immunofluorescence. We found that PCSM-LPD rarely harbored mutations recurrently detected in other T-cell neoplasms. PCSM-LPD is characterized by the invariable expression of the T-cell-receptor-associated LCK protein. CD70 and its ligand CD27 are co-expressed on PD1+ PCSM-LPD cells, suggestive of autoactivation of the CD70 pathway. In conclusion, PCSM-LPD differs from disseminated lymphomas of Tfh origin by their mutation profile. Activation of CD70 signaling also found in cutaneous T-cell lymphoma represents a potential driver of neoplastic proliferation of this benign neoplasia of Tfh. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.     

CD70 represents the human ligand for CD27

The recently identified CD27 ligand (L) Is a type II transmembranemolecule with significant structural homology to tumor necrosisfactor (TNF)-, TNF-ß, lymphotoxin ß, CO40L,and CD30L. Using a CD27L specific mAb we examined the tissuedistribution of the molecule, and found Its expression to berestricted to B cells in occasional germinal centers, stromalcells in the thymic medulla, and scattered T cells in tonsils,skin and gut. As the limited expression of CD27L closely resembledthe reported distribution of the activation antigen CD70, wetested whether CD70 represents the human CD27L. CD70 mAb werefound to react with CD27L-expressing transfected mouse fibroblasts.Moreover a number of CD70 mAb could specifically interfere withthe cellular binding of CD27L mAb. Thus, CD70 Is Identical tothe human CD27L.     

Involvement of CD27/CD70 interactions in antigen-specific cytotoxic T-lymphocyte (CTL) activity by perforin-mediated cytotoxicity

CD27 molecules are shown to be essential in the regulation of the death, activation and differentiation of T and B cells. However, the influence of CD27 on cytotoxic T-cell function remains obscure. Autologous EBV transformed B-cell lines (LCL), which highly express CD27 ligand CD70, here stimulated T cells and induced the cytotoxic T-lymphocyte (CTL) activity via T-cell antigen receptors (TCR). The cytotoxicity against LCL was diminished when anti-CD70 blocking MoAb was added initially in the culture. Resting T cells killed more CD70-transfected P815 cells than wild type P815 cells in the presence of anti-CD3 MoAb as measured by a 4-h 51Cr release assay, and the cytotoxicity of both of the cell populations completely disappeared in the presence of concanamycin A (CMA). The expression of the perforin by the LCL-induced CTL in the presence of anti-CD70 blocking MoAb was diminished as compared with that without the blockage of CD27/CD70 interactions. The CTL induced by LCL did not kill Fas-transfected WR cells. CD27 signalling in the T cells did not affect Fas ligand (FasL) mRNA expression, LAK activity and IFN-gamma synthesis in humans. Our data demonstrate that CD27/CD70 interactions enhance the cytotoxicity of CTL in the induction phase through enhancement of killing activity induced via the perforin-dependent mechanism, but not via the Fas/FasL system.     

Effects of CD70 and CD11a in Immune Thrombocytopenia Patients

Introduction  

CD70 and CD11a are co-stimulatory molecules that are important for the immune functions of T, B lymphocytes. Over-expressions of CD70 or CD11a cause T cell to be autoreactive.     

IL-7 modulates B cells survival and activation by inducing BAFF and CD70 expression in T cells

Interleukin-7 (IL-7) promotes the maintenance and activation of peripheral T cells, whereas it does not act directly on mature B cells due to the lack of IL-7Rα expression on these. We report here that, in spite of the insensitivity of B cells to IL-7, high concentration of IL-7 can lead to increased B cell survival and antibody production in the presence of T cells, without the use of any further B cell stimulatory signal. IL-7 promoted B cell activation through inducing CD70 expression on resting T cells, particularly on CD4+ memory cells. The interaction of CD70 molecules with the B cell costimulatory receptor CD27 led to B cell proliferation, the accumulation of CD38 + CD20- plasmablasts and antibody production. In addition, IL-7 treatment induced BAFF secretion from resting peripheral T cells thereby promoting B cell survival. IL-7 levels can increase in lymphopenic conditions, in autoimmune diseases or in patients receiving T cell regenerative IL-7 therapy. Based on our findings high IL-7 levels can lead to increased B cell activation by inducing the B cell regulatory proteins CD70 and BAFF in resting T cells. Such activity might be beneficial in short term immune-stimulatory IL-7 therapies; permanently increased IL-7 levels, on the other hand, can contribute to impaired B cell tolerance.     

CD27-CD70在淋巴细胞中的作用

CD27及其配体CD70属于肿瘤坏死因子-肿瘤坏死因子受体超家族,是一对共刺激分子,在T、B、NK细胞的活化、增殖中起重要作用,而且CD27通过CD70可精确地调节免疫应答的程度和持续的时间.CD27被认为是CD4+CD25+细胞(Tr)的一个标记,可以鉴别调节性和非调节T细胞;CD27在B细胞上的表达可促进生发中心的形成并存在于记忆性B细胞上.CD27分子参与调节NK细胞的增殖与活化,可能与NK细胞的自然免疫监视及NK细胞主动攻击表面表达CD70的病毒感染细胞及突变细胞密切相关.而体内体外试验均表明CD70是B细胞上的一个抑制信号,CD70可抑制浆细胞的形成,且树突状细胞上CD70的功能不能被其它共刺激分子所替代.CD27-CD70有可能成为自身免疫性疾病又一个新的治疗靶点.     

CD27/CD70 interaction directly drives B cell IgG and IgM synthesis

CD27 is a T cell activation antigen expressed on a majority of peripheral blood T cells. CD27 is also expressed on a subpopulation of human B cells, and it is reported that CD27⁺ B cells secrete both IgG and IgM. CD70, a ligand for CD27, is expressed on activated T and B cells, suggesting an interaction between T and B cells via CD27/CD70 ligation. Here, we analyze B cell immunoglobulin synthesis using a CD70 transfectant and present functional data showing that B cells secrete large amounts of IgG and IgM as a result of the CD27/CD70 interaction. A flow cytometric analysis showed that CD27 expression was increased and CD70 was expressed on tonsillar and peripheral blood B cells after activation with Staphylococcus aureus Cowan strain (SAC) plus interleukin (IL-2). In addition, the proliferation of B cells was enhanced mildly by the addition of CD70 transfectant, and its proliferation was blocked by anti-CD70 mAb. More importantly, the CD70 transfectant enhanced IgG and IgM production by purified B cells greatly in the presence of SAC plus IL-2. The enhancement was completely blocked by the addition of either anti-CD70 mAb or anti-CD27 mAb. Strongly suggesting that the interaction of CD27 with its ligand, CD70, on B cells plays an important role in B cell growth and differentiation to produce IgG and IgM.     

CD27-CD70轴与自身免疫性疾病的关系

CD27-CD70共刺激信号途径是除了经典CD28-CD80/86轴外,初始T细胞活化第二个重要的共刺激信号途径.CD70-CD27轴为T、B细胞提供刺激信号、调节其免疫应答.对CD27-CD70轴的作用及与自身免疫性疾病关系的研究,有助于更加了解自身免疫性疾病的发病机制,为免疫治疗提供新思路.     

Phenotype and function of human B cells expressing CD70 (CD27 ligand)

CD70, the cellular ligand of the tumor necrosis factor receptor family member CD27, can be found on a limited number of germinal center (GC) B cells in some tonsils, on scattered lymphocytes residing in secondary lymphoid organs, and on a fraction of the circulating B cell population. Due to the restricted expression of CD70 in vivo, we analyzed signals that determine CD70 expression levels and characterized the phenotype and function of CD70⁺ B cells. Expression of CD70 on B cells activated in vitro was found to be dependent on the continuous presence of a B cell antigen receptor cross-linking agent, and induced or potentiated by CD40 ligation but was down-modulated by the Th2 cytokines interleukin (IL)-4 and IL-13. Both in peripheral blood and tonsil cell suspensions, CD70⁺ B cell subpopulations were found to be enriched for CD27-and IgG-expressing cells, but contained less IgD⁺ B cells. Additional analysis of markers which define specific differentiation stages (Bm1-5) of mature B cells within human tonsils did not place CD70-expressing B cells in one of these subsets. Functional experiments revealed that whereas both CD70⁻ and CD70⁺ B cells can secrete immunoglobulin after activation with a combination of Staphylococcus aureus Cowan strain I and IL-2, only CD70⁺ B cells can produce large quantities of antibodies when stimulated in a T cell-dependent fashion. Our combined data imply that CD70 is a marker for mature B cells which have recently been primed by antigen in vivo.     

CD154-CD40 interactions in the control of murine B cell hematopoiesis

Interactions between CD40 and CD154 play a very important role in control of immune responses, including the delivery of T cell help to B cells and other APCs. Thus far, there has been no role postulated for CD40-CD154 interactions in hematopoiesis. We show here that CD40 is expressed on murine pro-B cells and that its ligation enhances pro-B cell proliferation in vitro and in vivo. In addition, CD154 mRNA is present in the BM. Moreover, we show that a deficiency in CD154 expression has effects on B cell hematopoiesis. Aged, CD154-deficient mice have significantly lower levels of B hematopoietic subsets downstream of pro-B cells in the BM. In addition, B lineage cells reconstitute more slowly following BMT into CD154-deficient recipients. We hypothesize that CD154 is expressed by radio-resistant cells in the BM and plays a role in fine-tuning B cell hematopoiesis.     

CD27/CD70 interaction directly induces natural killer cell killing activity.

The CD27 molecule is expressed on a portion of natural killer (NK) cells as well as T and B cells. To provide the functional capacity of CD27 molecule on NK cells, we here highly purified CD3- CD56+ NK cells by flow cytometry (purity > 98%), and investigated their NK cell activity via CD27/CD70 interaction using a CD70-transfectant by a 4 h 51Cr-release assay. The enhancement of NK activity by purified NK cells in the presence of interleukin-2 (IL-2) or interleukin-12 (IL-12) against CD70/Nalm-6 was not recognized as compared to against mock/Nalm-6. However, after a coculture with the fixed CD70/300-19, the purified NK cells increased the NK cell activity against K562, the value being 10 to 20% higher than coculture with the mock/300-19 in the presence of IL-2 or IL-12. The enhancement of NK activity was blocked by the addition of anti-CD70 monoclonal antibody (mAb). In addition, conjugation of NK cells to the target was increased by coculture with the CD70/300-19 without increased expression of adhesion molecules. In the parallel experiment, there was no increase in the killing capacity of NK cells. These results strongly show that CD27/CD70 interaction directly enhances NK activity in the presence of IL-2 or IL-12 by increasing the effector and target conjugate formation, indicating that CD27/CD70 interaction plays an important role in the cytotoxic function of NK cells.     

CD44 and CD27 delineate B-precursor stages with different recombination status and with an uneven distribution in nonmalignant and malignant hematopoiesis

The expression of CD27 and CD44 correlate with the genotype of B-precursor acute lymphoblastic leukemia (ALL). Based on the expression of these antigens, we identified counterparts of TEL/AML1(pos) and TEL/AML1(neg) leukemic cells in nonmalignant bone marrow. Although CD27 is known as a marker of mature memory B cells, we recently showed that CD27 is also expressed by malignant and nonmalignant B precursors. Here, we show that CD27 and CD44 delineate stages of B-precursor development. Well-established differentiation markers showed that the developmental sequence starts from undetermined progenitors, expressing CD44. Upon B-lineage commitment, cells gain CD27 and lose CD44. The CD27(pos)CD44(neg) (CD27 single positive, 27SP) cells are the earliest stage within CD10(pos)CD19(pos) B precursors and express RAG-1 and TDT. These cells correspond to TEL/AML1(pos) ALL (1/4 pediatric B-precursor ALL). The development follows to CD27/CD44 double-positive (27/44DP) stage, 44SP stage and CD27/CD44 double-negative (27/44DN) stage. Before exit to periphery, CD44 is reexpressed. The 27/44DP cells are mostly large and profoundly suppress RAG-1. Despite their presumably high proliferation potential, 27/44DP cells rarely dominate in leukemia. At 44SP stage, which corresponds to TEL/AML1(neg) leukemias, RAG-1 is reexpressed and Ig light chain gene starts to be rearranged.     

Migration through basement membrane modulates eosinophil expression of CD44

BACKGROUND: Tissue eosinophils express more membrane receptors and release more mediators than blood eosinophils, suggesting that migration from blood to tissue modulates eosinophil phenotype and functions. OBJECTIVE: We postulated that eosinophil passage through endothelial basement membrane, an important step of eosinophil migration into tissue, may be responsible for some of these changes. METHOD: We previously showed that 5-oxo-6, 8, 11, 14-eicosatetraenoic acid (5-oxo-ETE) in combination with IL-5 promotes eosinophil migration through Matrigel, a mouse tumour cell-derived basement membrane. Using this model, we evaluated the effect of trans-Matrigel migration on purified human blood eosinophil expressions of CD44, CD69 and HLA-DR that either increase or appear on activated eosinophils, and releases of peroxidase (EPO), leukotriene (LT) C(4) and granulocyte-monocyte colony stimulating factor (GM-CSF). RESULTS: IL-5, but not 5-oxo-ETE, increased eosinophil expression of CD44 and CD69. Migration of eosinophils through Matrigel significantly increased CD44 expression level over the one induced by IL-5 (P = 0.0001). Migration through Matrigel did not modify CD69 expression compared with the one obtained in the presence of IL-5 alone; however, incubation of eosinophils on Matrigel decreased IL-5-induced CD69 (P = 0.0001). Trans-Matrigel migration did not modify HLA-DR expression, nor EPO, LTC(4) and GM-CSF releases. CONCLUSION: These data show that in vitro trans-Matrigel migration and Matrigel contact modulate eosinophil membrane receptor expression. Consequently, they suggest that migration through basement membrane mediates changes in cell-surface phenotype observed on activated eosinophils and probably prepares them for interactions with tissue components and cells.