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Biomedical subjects

C E Grossi

Publications and source records attributed to C E Grossi.

At least 37 records · Page 2Linked to original sources
PubMed1997

HIV is trapped and masked in the cytoplasm of lymph node follicular dendritic cells.

To gain further insight into the pathogenesis of human immunodeficiency virus (HIV) infection, lymph nodes from seven asymptomatic HIV+ subjects were analyzed during the latent phase of disease. Both ultrastructural and immunohistochemical analyses revealed that, in all of the cases, plasma cells producing IgM/gamma were present in germinal centers. Secreted immunoglobulins formed extracellular deposits mimicking the follicular dendritic cell network. Immunoglobulin produced by germinal center plasma cells are specific for HIV because they bind the HIV env protein gp 120. Plasma cells producing antibodies with the same specificity were also abundant in the extrafollicular regions of lymph nodes. During the latent phase of infection, the virus largely accumulates within the germinal centers. Therefore, extracellular immunoglobulin may form immune complexes, as shown by the presence of HIV-specific antibodies, HIV particles, and complement components C3c, C3d, and C1q in the interdendritic spaces. When the ultrastructural localization of HIV in germinal centers was analyzed, abundant virus particles were found in the interdendritic spaces. In addition to this extracellular localization of HIV, receptor-mediated endocytosis of viral particles by follicular dendritic cells was observed. Complete HIV particles were found within the endosomal compartment of the follicular dendritic cells and, as complete viral particles, free in the cytoplasm, indicating that the virus may escape from the endocytic compartment. As the virus is abundant in the cytoplasm, this event leads to formation of a hidden reservoir within follicular dendritic cells. In this location, HIV escapes recognition by cytotoxic T lymphocytes. In contrast, virus budding indicating a productive infection of follicular dendritic cells that would render them susceptible to T-cell-mediated lysis has been seldom observed.

Antigen-Antibody Complex↗
PubMed1996

Apoptosis of Burkitt's lymphoma cells induced by specific interaction of surface IgM with a self-antigen: implications for lymphomagenesis in acquired immunodeficiency syndrome.

In a previous study, we described a cell line (BRG-P) derived from a woman with Burkitt's lymphoma (BL) and acquired immunodeficiency syndrome that shared the same characteristic cytogenetic abnormalities as the patient's malignant cells. This cell line contained subclones that displayed an isotype switch from IgM to IgA1 and an accumulation of point mutations in the Vh region genes. Because these two features suggested an antigen-driven process, we began a search for the antigen responsible for the stimulation of the malignant B cells. Specifically, we hypothesized that because the patient's tumor had presented as a lymphomatous infiltration of the breast, the malignant B cells were recruited to this site because of the reactivity of their surface lg with breast tissue. A hybridoma (BRG-H) was obtained by fusing BRG-M cells (an IgM producing subclone of the BRG-P cell) with an appropriate cellular partner. The monoclonal antibody (BRG MoAb) produced by this hybridoma reacted strongly with two of five breast cancer cell lines and stained normal and malignant ductal epithelial cells on breast tissue sections. The antigen recognized by the BRG MoAb consisted of a single, minimally glycosylated polypeptide chain of 45 kD (p45). The BRG MoAb failed to react with a panel of human cell lines from different tissues, except for one cell line from a uterine cervical carcinoma. No reactivity was detected for a panel of exogenous antigens from various pathogens, including human immunodeficiency virus and self-antigens frequently recognized by polyspecific antibodies. Experiments were performed to investigate the functional consequences of the interaction of surface IgM with its specific ligand. Coculture of BRG-M cells with p45+, but not with p45-, breast cells caused apoptosis of BRG-M cells. The specificity of the interaction was shown by the observation that apoptosis was prevented by pretreatment of BRG-M cells with a monovalent F(ab') fragment of rabbit IgG antibody to human mu chains. Moreover, only BRG-M cells, but not other BL cells, underwent apoptosis after exposure to p45+ breast cells. The interaction between the CD40 molecule expressed by BRG-M cells and its specific ligand (CD40L) prevented p45-induced cell apoptosis. Because this interaction mimics that occurring in vivo between T and B cells during immune responses, our data suggest that various events contributed to the emergence of the BL, in this particular patient, including antigenic stimulation possibly assisted by T-cell help.

Adult↗
PubMed1996

Natural killer (NK)-cell function and antileukemic activity of a large population of CD3+/CD8+ T cells expressing NK receptors for major histocompatibility complex class I after "three-loci" HLA-incompatible bone marrow transplantation.

We have shown that addition of granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to the marrow inoculum allows engraftment of T-cell depleted, "three loci" HLA-incompatible marrow transplants for acute leukemia. The event-free survival of patients at high risk for potential of this transplant. Tumor-cell lysis by natural killer (NK) cells is regulated by inhibitory receptors for specific HLA class I alleles. Here, we report the postgrafting emergence of a large, donor-type CD3+/CD8+ T-cell receptor (TcR)-alpha beta+ cell population, barely detectable in normal subjects, that expresses 58 kD, "p58," NK receptors for HLA-C locus alleles. Analysis of > 900 clones revealed that 40% to 80% of these T cells exhibit NK-like function, i.e., they lysed class I- targets and were functionally blocked by class I alleles on target cells. Monoclonal antibody-mediated blocking of class I recognition by these cells induced lysis of HLA-protected, autologous targets. The class I-mediated inhibitory signaling through the NK receptors also blocked TcR/CD3-triggered cytotoxicity of these cells, indicating that their antigen-specific responses may be impaired. However, the NK-like function of these cells allows them to discriminate normal cells, protected from lysis, from leukemic cells that were lysed and may be targets for a graft-versus-leukemia effect.

Acute Disease↗
PubMed1996

Subepithelial B cells in the human palatine tonsil. I. Morphologic, cytochemical and phenotypic characterization.

This study describes the purification of a subset of tonsillar B cells which share phenotypic, morphologic and cytochemical features with subepithelial (SE) B cells. These cells, which represented the 5-10% of the total tonsillar B cells, were found in the Percoll gradient fraction of highest density, together with resting follicular mantle (FM) B cells. The latter B cells, however, expressed surface CD5 and could be removed by an immune rosetting procedure. The remaining small CD5- B cells had a surface phenotype (IgM+, IgD+, CD23-, CD38+/-, CD10-, CD44+) that was different from that of FM (IgM+, IgD+, CD23+, CD39+, CD38-, CD10-, CD44+2) and of germinal center (GC) (CD23-, CD39-, CD38+, CD10+, CD44+/-, IgG+) B cells isolated from the same cell suspensions. Furthermore, the absence of surface activation markers (CD71 and CD69) and of surface IgG allowed us to distinguish small CD5- B cells from activated and memory cells migrating within Percoll fractions of lower density. In situ immunohistochemical studies revealed that B cells with an identical phenotype as that of small CD5- B cells could be detected predominantly in the SE region (lamina propria) of the tonsil, and also within the epithelium lining the cryptae. This area was also comprised of a relatively minor proportion of activated B cells, not found in the small CD5- B cell fraction owing to the separation procedure used. Consistent with the notion that the SE area could be a site of B cell activation was also the presence of activated macrophages and of plasma cells. Thirty to forty percent of small CD5- B cells isolated in suspension were positive for the endogeneous alkaline phosphatase (ALP) activity. In contrast, only a few FM B cells were ALP+, while GC cells were consistently ALP-. In situ studies also demonstrated a prevalent expression of ALP activity by the B cells in the SE area. At the ultrastructural level, small CD5- B cells were clearly different from both FM and GC B cells. They displayed a cytoplasm more extended than that of FM B cells with abundant endosomes and plasma membrane projections, and a speckled pattern of nuclear heterochromatin distribution. When fixed tissue sections were examined, cells with identical ultrastructural features could be demonstrated in the tonsillar lamina propria. Collectively, the above data demonstrate an identity of features between the small CD5- B cells isolated in suspension and SE B cells analyzed in situ. Since tonsillar SE B cells are generally thought to represent the homolog of the extrafollicular B cells (including those of the splenic marginal zone), these studies may provide new opportunities for functional studies on this so far incompletely characterized B cell subset.

Alkaline Phosphatase↗
PubMed1996

Subepithelial B cells in the human palatine tonsil. II. Functional characterization.

This study investigates the main functional features of subepithelial (SE) B cells and compares them with those of purified germinal center (GC) and follicular mantle (FM) B cells isolated from the same tonsils. Unlike FM B cells, SE B cells failed to produce polyspecific antibodies in vitro; unlike GC B cells, SE B cells expressed high levels of Bcl-2 and failed to undergo spontaneous apoptosis in vitro. The most striking function of SE B cells was their ability to produce IgM antibodies to T cell-independent type-2 (TI-2) (but not to TI-1) antigens (Ag). These antibodies could not be detected when both FM and GC B cells were stimulated with TI-2 Ag in vitro. Moreover, B cells isolated from peripheral blood were unable to mount a response to TI-2 Ag. The latter finding is consistent with the observation that B cells with the phenotypic features of SE B cells were virtually absent in the peripheral blood and emphasizes the notion that SE B cells belong to a subset of non-recirculating B cells. SE B cells were by far superior to FM B cells in mixed lymphocyte reaction (MLR) stimulation of allogeneic T cells in vitro, although they were not as efficient as dendritic cells (DC). In order to stimulate T cells efficiently, SE B cells had to be exposed to anti-mu antibody, a treatment which induced expression of activation markers such as CD80, CD86, CD69 and CD39, usually absent in resting SE B cells. CD80 and CD86 molecules expressed by SE B cells participated in the chain of events required to promote the proliferation of allogeneic T cells as demonstrated by inhibition tests with the appropriate mAb. The expression of CD80 and CD86 by anti-mu-treated SE B cells was not, however, the sole explanation for their good antigen presenting capacities since the exposure of FM B cells to anti-mu antibody also induced expression of these surface structures. Nevertheless, these cells failed to become good MLR stimulators. Collectively, the above data contribute further to the characterization of a distinct subset of tonsillar B cells which resemble, both phenotypically and functionally, the B cells of the splenic marginal zone.

Animals↗
PubMed1995

Involvement of CD44 variant isoforms in hyaluronate adhesion by human activated T cells.

The standard, 85-95-kDa form of the hyaluronic acid (HA) receptor CD44 and a number of CD44 mRNA splice variants play important roles in immune responses and tumor metastasis. Variants carrying exon 6 (v6), or 9 (v9) products are transiently expressed on activated human T cells. Here, modulation experiments with specific monoclonal antibodies (mAb) indicate that v6 and v9 are expressed independently on distinct sets of CD44 molecules, and that their combined expression is necessary for HA adhesion. Moreover, the finding that mAb-mediated cross-linking of v6 and v9 promoted cytosolic free Ca2+ mobilization and co-stimulated CD3-triggered T cell proliferation indicates that v6 and v9 possess signaling and effector function activation ability. Finally, HA-mediated signaling appears to be required for variant-dependent adhesion to HA. The observation that soluble HA promoted cytosolic free Ca2+ mobilization indicates that HA-induced Ca2+ mobilization can occur during T cell-HA interaction. Since Ca2+ mobilization was inhibited by pretreatment of cells with an anti-CD44 mAb directed against the HA-binding domain of CD44, CD44 receptors appear to be involved in HA-mediated signal transduction. The requirement of cytosolic free Ca2+ for adhesion is shown by the fact that ionomycin (a Ca2+ ionophore) stimulated, and EGTA (a Ca2+ chelator), inhibited HA adhesion. In addition, cytoskeletal functional activation is required for cell adhesion to HA, since drugs that block actin polymerization, such as cytochalasin B, or actomyosin contraction, such as the calmodulin antagonist W-7, inhibited cell adhesion to HA. As this adhesion is also ADP ribosylation-sensitive, it may involve a GTP-dependent function of CD44v, i.e. ankyrin binding. Our data indicate that there is a functional hierarchy among the CD44 molecules expressed on human peripheral blood T cells and that the splice variants, as compared to the standard form, exhibit a greater HA binding ability which involves CD44-mediated signaling and effector function activation.

Actins↗
PubMed1995

Expression of a novel beta 1 integrin in the dysplastic progression of the cervical epithelium.

Epithelial cell interactions with matrices and basal membranes are central for tissue organization, and integrins are a family of adhesion molecules that play a major role in these interactions. We have analyzed the expression of a novel integrin alpha chain, alpha 10.1.2, in the squamous epithelium of the portio vaginalis uteri from patients with cervical intraepithelial neoplasia (CIN) and from control samples without apparent cervical abnormalities. The localization of beta 1 and alpha 6 chains was also investigated, together with the distribution of intraepithelial HLA-DR and CD1c-positive Langerhans cells. In the normal cervical epithelium, all of the integrin chains were detected in the basal cell layer, albeit with a different localization in the apical, lateral, and basal cell surfaces. Langerhans cells were evenly distributed in the deep 2/3 of the squamous epithelium. Expression of alpha 10.1.2 was reduced or absent in all of the CIN 1 specimens in which the other integrin chains were either normal or slightly reduced. CIN 2 was characterized by overexpression of integrins, namely of beta 1 and of alpha 10.1.2 chains which were consistently detected also in suprabasal cell layers. None of the integrin chains was found in CIN3 samples in which Langerhans cells were also absent. Thus, modulation and redistribution of integrins occur in the progression of cervical dysplasia, and lack of integrin expression characterizes high-grade lesions. As in other dysplasias and cancers of squamous epithelia, the localization of alpha 10.1.2 chains provides reliable diagnostic and possibly prognostic criteria.

Adult↗
PubMed1995

Biochemical characterization and membrane expression of an antigen shared by activated and neoplastic cells of neuroectodermal origin.

The reactivity of a mAb (M16) raised against a small cell lung carcinoma line is described. M16 identifies a surface antigen expressed on cells of neuroectodermal origin following activation, as well as neoplastic transformation. M16 antigen expression is increased on retinoblastoma and neuroblastoma cell lines upon 'in vitro' stimulation and it is induced 'in vivo' on glial cells activated following brain injury. Furthermore, glial tumors show levels of M16 molecule expression increasing with the degree of malignancy, and in a retinoblastoma cell line, the expression of M16 was inversely related to the level of HLA-Class I and N-CAM antigens. The M16 antigen may represent a marker of both activation and neoplastic progression for neuroectodermal cells.

Animals↗
PubMed1994

Hyaluronate is costimulatory for human T cell effector functions and binds to CD44 on activated T cells.

Lymphohematopoiesis, cell matrix adhesion, homing of leukocytes, T cell activation, and tumor metastasis are mediated through the CD44 family of cell surface receptors. We have recently shown that anti-CD44 mAb trigger protein tyrosine kinase-dependent activation of T cell effector functions. Here, we show that hyaluronate (HA), a CD44 ligand, in conjunction with CD3/TCR-mediated stimuli, is costimulatory for human peripheral blood T cell proliferation, for IL-2 production by Th clones, and for release of trypsin-like esterase by cytolytic T cell clones. A human T cell line, HUT-78, was found to bind HA and on HA coating it was used as a target for cytolytic T cell clones. After anti-CD3 stimulation, CD3+/CD8+ clones acquire the ability of lysing HA-coated HUT-78 cells more efficiently than the same HA-uncoated targets. Resting peripheral blood T cells and T cell clones do not adhere to HA-coated plates. However, 24-h anti-CD3 mAb stimulation gives them the transient ability to bind HA. HA adhesion of activated T cells and T cell clones, as well as that of T cell lines, is blocked by one anti-CD44 mAb (J-173). Two other anti-CD44 mAbs induce a 10-fold increase in HA adhesiveness of anti-CD3-stimulated peripheral blood T cells. This impressive HA adhesiveness is also readily blocked by J-173 anti-CD44 mAb. These data indicate that 1) HA is costimulatory for human T cell effector functions in conjunction with CD3/TCR-mediated stimuli, 2) the capacity to bind HA is acquired by resting T cells and T cell clones after anti-CD3 stimulation, and 3) HA binding occurs via specific interaction with CD44 molecules expressed on activated T cells.

CD4-Positive T-Lymphocytes↗
PubMed1994

Characterization of avian natural killer cells and their intracellular CD3 protein complex.

Natural killer (NK) cell activity appears to be conserved throughout vertebrate development but NK cells have only been well characterized in mammals. Candidate NK cells have been identified in the chicken as cytoplasmic CD3+ and surface T cell receptor (TCR)/CD3- (TCRO) lymphocytes that often express CD8. The fact that the TCRO cells are abundant in the embryonic spleen before T cells enter this organ allowed us to cultivate the embryonic TCRO cells using growth factors derived from activated adult lymphocytes. These TCRO cells were cytotoxic for an NK target cell line. They expressed cell surface CD8, a putative interleukin-2 receptor, CD45 and a receptor for IgG, but did not express CD4, major histocompatibility complex class II or immunoglobulin. Biochemical analysis of the cytoplasmic CD3 antigen revealed two of the three CD3 gamma, delta and epsilon homologues, and RNA transcripts for the third. The CD3 monoclonal antibody also precipitated a 32-kDa dimer that may represent a heterodimer of different CD3 constituents. TCR alpha and beta gene transcripts were not detected in the TCRO cells. These results indicate that the avian TCRO cell is the mammalian NK cell homologue. The shared evolutionary features of T cells and NK cells in birds and mammals support the idea that they derive from a common progenitor.

Animals↗
PubMed1994

Oncolytic activity of NK cells against SW-756 squamous cervical carcinoma cell line: role of interferons alpha and gamma and CD54 adhesion molecule in oncolysis.

We investigated the sensitivity of a cervical tumor cell line SW-756 to lysis by peripheral blood mononuclear cells (MNC), natural killer (NK) cells, and major histocompatibility complex (MHC)-nonrestricted (MHC-NR) T cells from cervical cancer patients and normal donors. We found that SW-756 was resistant to lysis mediated by naive (unstimulated) MNC and MHC-NR T cells, but sensitive to lysis by naive NK cells. However, the cytotoxic function of MNC could be activated with interleukin-2 (IL-2) and interferon (IFN) alpha or gamma. Although IFNs were effective in enhancement of effector cell cytotoxicity and inhibited proliferation of cervical tumor cells, they also exerted an adverse effect on cytotoxicity; specifically, pretreatment of SW-756 cells with IFNs significantly decreased their susceptibility to lysis by effector cells. Analysis of surface phenotype of SW-756 cells after treatment with IFNs showed up-regulation of expression of HLA class I determinants, the phenomenon that may be responsible for decreased sensitivity of this tumor to MHC-NR NK cells. The studies on the involvement of CD54 adhesion molecule in cytotoxic functions indicated that expression of this molecule on effector cells (but not on target cells) was important for cytotoxicity against SW-756 tumor cells. The therapeutic implication of these studies for patients with cervical cancer is discussed.

Carcinoma, Squamous Cell↗
PubMed1994

Immunohistochemical localization of a novel beta 1 integrin in normal and pathologic squamous epithelia.

The 10.1.2 MoAb reacts with a novel alpha chain that associates with the beta 1 integrin chain and is widely distributed among epithelial and endothelial cells of human adult and fetal tissues. In the epidermis and in other squamous epithelia, alpha 10.1.2 chains are expressed exclusively in the basal cell layer. Here we describe the immunohistochemical localization of alpha 10.1.2 in human epidermis, in other squamous epithelia, as well as in cultured keratinocytes. alpha 10.1.2 chain localization has also been investigated in a variety of non-neoplastic and neoplastic lesions of the skin, the uterine cervix, and the lung. We show that alpha 10.1.2 chains retain their basal keratinocyte localization in hyperplastic skin diseases and in benign tumors of the epidermis and that they are strongly expressed in basal cell carcinomas. In contrast, alpha 10.1.2 expression is decreased in keratinocytes that differentiate in vitro and is lost in epidermal dysplastic conditions, in the invading front of squamous cell carcinomas of the epidermis, in microinvasive cervical cancers, and in well-differentiated squamous lung tumors. These findings indicate that alpha 10.1.2 beta 1 integrin is downregulated during keratinocyte differentiation in vitro and in vivo. Moreover, lack of alpha 10.1.2 expression in basal cells of squamous epithelia is associated with early dysplastic changes and with the acquisition of invasive capacity.

Antibodies, Monoclonal↗
PubMed1994

Adhesion molecule expression on B-cells from acute and chronic lymphoid leukemias.

Adhesion molecule expression on acute and chronic lymphoid leukemia cells of B lineage (B-ALL and B-CLL) may subserve several functions. Adhesion of leukemic cells to endothelial cells and to extracellular matrix components is relevant to homing, trafficking and spread of the malignant cells, and thus to clinical presentation, course and disease prognosis. Adhesive interactions between malignant cells and accessory cells, particularly stromal cells in the bone marrow environment, may support growth of the malignant cells via cytokine-delivered messages. They may also deliver signals that prevent or trigger programmed cell death of tumor cells. Here we review data on the adhesive phenotype of leukemic blasts from pro-B (CALLA +) ALL and of cells from B-CLL cases. We show that expression of certain adhesion molecules may help define disease subsets with distinctive clinical and prognostic features. One adhesion molecule, the lymphocyte homing receptor CD44, allows definition of two groups of B-CLL patients with significantly different survival.

B-Lymphocytes↗
PubMed1993

Targeting of T lymphocytes against EGF-receptor+ tumor cells by bispecific monoclonal antibodies: requirement of CD3 molecule cross-linking for T-cell activation.

Targeting of T lymphocytes against epidermal growth-factor-receptor (EGF-R)+ tumor cells was achieved by constructing a hybrid hybridoma which secretes an anti-EGF-R/anti-CD3 bispecific monoclonal antibody (biMAb) of hybrid isotype (IgG1/IgG2a). Purification of biMAb molecules from parental anti-EGF-R and anti-CD3 MAbs was performed by protein-A chromatography. The purified biMAb was able to trigger the lysis of EGF-R+ tumor cell lines (A431, IGROV-1, MDA-468 and U-87) and of NIH-3T3 transfectants expressing human EGF-R by cytolytic T lymphocytes, but it was ineffective in the case of EGF-R-negative tumor targets. Normal EGF-R+ cells (keratinocytes and endometrial cells) were also susceptible to biMAb-targeted cytolysis. However, the amount of biMAb required to induce half-maximal cytolysis of tumor cells over-expressing the EGF-R molecule (A431) was considerably lower than that required to induce lysis of EGF-R+ tumor or normal cells which express EGF-R at considerably lower density. The ability of such biMAbs to deliver activation signals to T cells was evaluated by Ca++ mobilization and lymphokine production experiments. The soluble anti-EGF-R/anti-CD3 biMAb failed to induce intracellular Ca++ increases, which occurred only after cross-linking induced by an anti-mouse IgG antibody. Secretion of lymphokines (IFN-gamma, TNF-alpha and GM-CSF) was induced by contact of the biMAb-coated effector cells with the relevant tumor target, whereas the soluble biMAb was virtually ineffective. In addition, biMAb-coated effector cells retained the ability to recognize and to lyse EGF-R+ tumor cells for a prolonged period of time. Our data indicate that activation of effector cells targeted by biMAbs can only occur at the tumor site, where cross-linking of surface CD3 molecules is induced by contact with the tumor cells.

Antibodies, Bispecific↗
PubMed1993

Adhesion molecule expression on B-cell chronic lymphocytic leukemia cells: malignant cell phenotypes define distinct disease subsets.

Expression of surface adhesion molecules of the Ig superfamily (CD54 and CD58), of the integrin family (beta 1, beta 2, and beta 3 chains), of the selectin family (L-selectin), and of the lymphocyte homing receptor (CD44) was analyzed on B-cell chronic lymphocytic leukemia (B-CLL) cells from 74 patients. The aim of the study was the definition of phenotypically distinct disease subsets and the correlation of adhesion molecule phenotypes with clinical parameters. Expression of CD58 on B-CLL cells defined more advanced disease stages. In comparison with beta chain-positive cases, patients whose cells did not express beta 1, beta 2, and beta 3 integrin chains fell into the most favorable prognostic group, with lower lymphocytosis and the absence of splenomegaly, diffuse bone marrow infiltration, and therapy requirement. A novel finding was the expression of beta 3 chains on cells from a minority (12 of 74) of B-CLL cases. beta 3 chains were always coexpressed with beta 1 and beta 2 chains. Two-color immunofluorescence analyses of adhesion molecules such as alpha x beta 2 integrin (LeuM5) and L-selectin (Leu8) showed that these markers were detectable on variable proportions of leukemic cells, thus confirming the intraclonal phenotypic heterogeneity of B-CLL. Differences in the intensity of CD44 expression were also shown among the various B-CLL clones. Finally, no major variations were shown by comparison of adhesion molecule phenotypes of leukemic cells simultaneously obtained from blood and bone marrow, and of CD5+ versus CD5- clones.

Adult↗
PubMed1993

Antibodies to CD44 trigger effector functions of human T cell clones.

mAb against the lymphocyte homing receptor CD44/Hermes up-regulate the proliferation of human T PBL induced by anti-CD3 or anti-CD2 mAb. Moreover, certain anti-CD44 mAb can activate human resting T cells and mouse cytotoxic T cells in the absence of anti-CD3 or anti-CD2 mAb. Here, we show that anti-CD44 mAb trigger proliferation of human CD3+/CD4+ T cell clones in a fashion similar to that observed with mAb to CD3. Such an effect is IL-2-dependent, as shown by IL-2 production induced by anti-CD44 mAb and by complete inhibition of cell proliferation in the presence of anti-IL-2 antibodies or cyclosporin A. Moreover, anti-CD44 mAb trigger human cytolytic T cell clones to lyse Fc gamma-R+ P815 cells in the absence of additional stimuli. The magnitude of the cytolytic response induced by anti-CD44 mAb is comparable to that observed in the presence of anti-CD3 mAb for both CD4+ and CD8+ TCR-alpha/beta+ clones, and for V delta 1 or V delta 2 TCR-gamma/delta+ clones. By contrast, in CD3-/CD16+ NK cell clones, no cytolytic responses to anti-CD44 mAb could be observed. Granule trypsin-like esterase enzyme (granzyme) release by cytolytic T cell clones is induced by plastic-immobilized anti-CD44 mAb. Anti-CD44 mAb-triggered proliferation ([3H]thymidine incorporation) and cytotoxicity are blocked by the protein tyrosine kinase inhibitor, genestein. In addition, ligation of the CD44 molecule induces tyrosine phosphorylation of proteins identical, by molecular mass, to those phosphorylated after anti-CD3 mAb stimulation. Notably, anti-CD44 mAb does not induce tyrosine phosphorylation of a 21-kDa protein (the phosphorylated zeta-chain of the TCR molecular complex) typically observed upon anti-CD3 mAb stimulation. In conclusion, this study shows that the ligated CD44 molecule provides the necessary stimuli for a variety of T cell-mediated functions triggered via protein tyrosine kinase-dependent signal transduction pathways at least in part similar to those that follow stimulation of the CD3/TCR complex.

CD4-Positive T-Lymphocytes↗
PubMed1993

Ligation of the lymphocyte homing receptor CD44 triggers T-helper and cytolytic functions of human T cells.

We show that antibodies to the CD44 molecule trigger proliferation of human CD3+/CD4+ T-cell clones. Such effect is IL2-dependent, as shown by IL2 production induced by anti-CD44 mAb and by inhibition of cell proliferation in the presence of anti-IL2 antibodies or cyclosporin A (CsA). Moreover, anti-CD44 mAb triggered human cytolytic CD4+ and CD8+ TCR alpha/beta+ clones, and V delta 1 or V delta 2 TCR Y/delta+ clones to lyse Fc-gamma-R+ P815 cells and to release granule trypsin-like esterase enzymes. Anti-CD44 mAb-triggered proliferation and cytotoxicity were blocked by the PTK-inhibitor, genestein. In addition, ligation of the CD44 molecule induced tyrosine phosphorylation of proteins identical, by molecular weight, to those phosphorylated following anti-CD3 mAb-stimulation. Notably, anti-CD44 mAb does not induce tyrosine phosphorylation of a 21 kD protein (the phosphorylated zeta chain of the TcR molecular complex) typically observed upon anti-CD3 mAb stimulation.

Antibodies, Monoclonal↗