Biomedical subjects

R J Armitage

Publications and source records attributed to R J Armitage.

At least 37 records · Page 2Linked to original sources

PubMed1996

Transforming growth factor-beta 1 cooperates with anti-immunoglobulin for the induction of apoptosis in group I (biopsy-like) Burkitt lymphoma cell lines.

Group I Burkitt lymphoma (BL) cell lines, which retain the original biopsy phenotype, have been shown to enter apoptosis in response to a number of external stimuli including serum deprivation, thermal shock, addition of calcium ionophore, and ligation of surface immunoglobulin (Ig) by antibody. Transforming growth factor-beta 1 (TGF beta 1) is known to cause growth arrest in BL lines. Here we show that while it is by itself capable of promoting some degree of apoptosis in group IBL cells, TGF beta 1 cooperates with anti-immunoglobulin to this end. Trimeric soluble recombinant human CD40 ligand (sCD40L) was able to inhibit apoptosis induced by the combination of agonists to some degree, but such rescue proved to be short-lived. Both TGF beta 1 and anti-Ig individually caused BL cells to undergo growth arrest at the G1 phase of cell cycle before their entry into apoptosis: the consequence of sCD40L addition was to maintain the cells in cycle for longer. No induction of the apoptosis-protecting gene, bcl-2, occurred in the presence of sCD40L. These findings are discussed, particularly highlighting the relationship existing between survival and the cell cycle. The strong cooperative effects observed between anti-Ig and TGF beta 1 in promoting apoptosis and the inability of CD40 to signal for long-term rescue raise the potential for a novel therapeutic attack on B-cell lymphoma.

Animals↗

PubMed1996

VH repertoire in human B lymphocytes stimulated by CD40 ligand and IL-4: evidence for positive and negative selection mechanisms coupled to CD40 activation.

In the normal immune system, B cells are thought to be negatively or positively selected at various checkpoints during their maturation; a process that maintains a broad immunoglobulin repertoire while eliminating non-functional or potentially harmful autoreactive antibodies. This study tested the hypothesis that utilization of certain immunoglobulin heavy chain variable region (VH) genes, possibly as a consequence of intrinsic affinity for various ligands, directs positive or negative B cell selection coupled to B cell activation in the periphery during the immune response. The specific prediction that the VH repertoire of CD40-activated B cells would differ from the repertoire of unstimulated cells from the same donor, was tested by assessing VH utilization among human B cell clones grown in vitro, following stimulation with CD40 ligand (CD40L) and IL-4. The results showed that, although utilization of the known VH families and of individual VH3 genes was similar to that found in unstimulated B lymphocytes of the same donor, utilization of individual VH4 genes in CD40-activated B cells displayed a pattern that was markedly different from that of the unstimulated B cells. An allele of V4-61, V4-61b, was over-represented among the activated cells and, in contrast, the V4-34 gene (known to encode cold agglutinins with strong autoreactive properties) was modestly represented among the VH4 activated B cells, although V4-34 was overwhelmingly predominant in the repertoire of resting B cells. These results point to the existence of selection mechanisms that operate during B cell activation in the periphery. These mechanisms may favor B cells utilizing certain VH genes and disfavor the cells that utilize other genes, possibly because utilization of the latter confers autoreactivity.

Adult↗

PubMed1996

The extracellular domain of the Epstein-Barr virus BZLF2 protein binds the HLA-DR beta chain and inhibits antigen presentation.

The Epstein-Barr virus BZLF2 gene encodes a glycoprotein that associates with gH and gL and facilitates the infection of B lymphocytes. In order to determine whether the BZLF2 protein recognizes a B-cell-specific surface antigen, a soluble protein containing the extracellular portion of the BZLF2 protein linked to the Fc portion of human immunoglobulin G1 (BZLF2.Fc) was expressed from mammalian cells. BZLF2.Fc was used in an expression cloning system and found to bind to a beta-chain allele of the HLA-DR locus of the class II major histocompatibility complex (MHC). Analysis of amino- and carboxy-terminal deletion mutants of the BZLF2.Fc protein indicated that the first 90 amino acids of BZLF2.Fc are not required for HLA-DR beta-chain recognition. Site-directed mutagenesis of an HLA-DR beta-chain cDNA and subsequent immunoprecipitation of expressed mutant beta-chain proteins using BZLF2.Fc indicated that the beta1 domain, which participates in the formation of peptide binding pockets, is required for BZLF2.Fc recognition. The addition of BZLF2.Fc to sensitized peripheral blood mononuclear cells in vitro abolished their proliferative response to antigen and inhibited cytokine-dependent cytotoxic T-cell generation in mixed lymphocyte cultures. Flow-cytometric analysis of Akata cells induced to express late Epstein-Barr virus antigens indicated that expression of BZLF2 did not result in reduced surface expression levels of MHC class II. The ability of BZLF2.Fc to bind to the HLA-DR beta chain suggests that the BZLF2 protein may interact with MHC class II on the surfaces of B cells.

Amino Acid Sequence↗

PubMed1995

Human IL-17: a novel cytokine derived from T cells.

A cDNA encoding human IL-17 (hIL-17) was cloned from a CD4+ T cell library. The predicted 155-amino acids sequence contains an N-terminal signal peptide and exhibits 72% amino acid identity with HVS13, an open reading frame from a T-lymphotropic Herpesvirus saimiri, and 63% with murine CTLA8. High levels of hIL-17 were induced from primary peripheral blood CD4+ T cells upon stimulation. When expressed in CV1/EBNA cells, recombinant hIL-17 was secreted in both glycosylated and nonglycosylated forms. A hIL-17.Fc fusion protein and supernatants from cells transfected with hIL-17 induced IL-6 and IL-8 production and enhanced the surface expression of the intracellular adhesion molecule-1 (ICAM-1) in human fibroblasts.

Amino Acid Sequence↗

PubMed1995

Antibodies to CD40 prevent Epstein-Barr virus-mediated human B-cell lymphomagenesis in severe combined immune deficient mice given human peripheral blood lymphocytes.

CD40 is expressed on both normal and neoplastic B lymphocytes. Signal transduction through CD40 in vitro has been shown to exert stimulatory effects on normal B cells and inhibitory effects on Epstein-Barr virus (EBV)-induced B-cell lymphoma lines and some other cell lines derived from patients with aggressive histology lymphoma. The transfer of normal human peripheral blood lymphocytes (huPBL) from EBV-seropositive donors into severe combined immune deficient (SCID) mice has been previously shown to result in the generation of human B-cell lymphomas. These tumors are similar to the highly aggressive EBV-induced lymphomas that can arise clinically after transplantation or in the setting of immunodeficiency. Treatment of huPBL-SCID chimeric mice with anti-CD40 or anti-CD20 monoclonal antibodies (MoAb) significantly delayed the development of EBV-induced B-cell lymphoma. However, the effects of the two MoAb were mechanistically distinct. Anti-CD40 treatment prevented lymphoma generation, while still allowing for functional human B-cell engraftment in the huPBL-SCID mice compared with mice receiving no treatment, all of which succumbed to lymphoma. By contrast, treatment with anti-CD20 significantly inhibited total human B-cell engraftment in the SCID recipients, which accounted for the absence of lymphomas. In vitro assays examining the transformation of human B cells by EBV also indicated that anti-CD40 could directly inhibit EBV-transformation, whereas anti-CD20 antibodies had no effect. Thus, anti-CD40 exerts selective effects to allow for the engraftment of normal human B cells and prevent the emergence of EBV lymphomas. Stimulation of CD40 by antibodies or its physiologic ligand may, therefore, be of significant clinical use in the prevention of EBV-induced B lymphomas that may arise when EBV-seropositive individuals receive immunosuppressive regimens after transplantation or in immune deficiency states, such as acquired immune deficiency syndrome.

Animals↗

PubMed1995

IL-15 has stimulatory activity for the induction of B cell proliferation and differentiation.

The identification and cloning of the novel cytokine IL-15 were recently described. IL-15 is produced by a wide range of cell types, with the highest levels of IL-15 mRNA being detected in epithelial lines, monocytes, muscle, and placenta. Although it has no sequence identity with IL-2, IL-15 shares many of the T cell-stimulatory activities described for IL-2. We have examined IL-15 for its ability to stimulate B cells and have compared its activity with that of IL-2. IL-15 costimulates proliferation of B cells activated with immobilized anti-human IgM or phorbol ester, but has no stimulatory effect on resting B cells. In combination with recombinant CD40L, IL-15 is a potent inducer of polyclonal IgM, IgG1, and IgA secretion, but does not cause production of IgG4 or IgE. The activity of IL-15 in B cell proliferation and differentiation assays is comparable with that of IL-2. Studies that used neutralizing Abs have demonstrated that, for signal transduction in B cells, IL-15 uses the beta-chain of the IL-2R complex but, unlike IL-2, does not require the alpha-chain. IL-2 is required for the generation of a human primary Ag-specific in vitro response using sheep erythrocytes as Ag. Of all cytokines examined, only IL-15 has the capacity to replace IL-2 in this system, although only partially. In summary, IL-15 has comparable activity with IL-2 for the induction of B cell proliferation and differentiation and uses at least some of the components of the IL-2R complex to mediate its effects.

Antibody Formation↗

PubMed1995

Function of the interleukin-2 (IL-2) receptor gamma-chain in biologic responses of X-linked severe combined immunodeficient B cells to IL-2, IL-4, IL-13, and IL-15.

The interleukin-2 (IL-2) receptor gamma-chain is a common component of several members of the cytokine receptor superfamily including those for IL-2, IL-4, IL-7, IL-9, IL-15, and possibly IL-13, and has recently been renamed the common gamma-chain (gamma c-chain). Transfection experiments have shown that the gamma c-chain participates in signal transduction by IL-2, IL-4 and IL-7, but a functional role for the gamma c-chain in biological responses by normal T cells and B cells to these cytokines has not been established. In this study, we have used X-linked severe combined immunodeficiency (X-SCID) as a naturally occurring gamma c-chain gene disruption model to examine the role of the gamma c-chain in human B-cell responses to IL-2, IL-4, IL-13, and IL-15. Our experiments show that B cells from two X-SCID patients with characterized gamma c-chain gene mutations do not respond to IL-2 or IL-15, but respond as well or better than normal B cells to both IL-4 and IL-13 in assays for B-cell activation, proliferation, and IgE secretion. This finding raises important questions about the function of the gamma c-chain in receptors for IL-4 and IL-13, and the nature of the immune defect in X-SCID.

B-Lymphocytes↗

PubMed1995

Recombinant CD30 ligand and CD40 ligand share common biological activities on Hodgkin and Reed-Sternberg cells.

The CD30 ligand (CD30L) and CD40L are members of the tumor necrosis factor (TNF) protein superfamily, CD30L and CD40L are mainly expressed as membrane-bound proteins by activated T cells. CD30L and CD40L are costimulatory for T cell proliferation and activation. Further, CD40L is a critical signal for T cell-dependent activation of B cells. Primary and cultured Hodgkin and Reed-Sternberg (H-RS) cells, the neoplastic component of Hodgkin's disease (HD), express high levels of the counterreceptors CD30 and CD40. We have found that both the recombinant CD30L and CD40L enhanced interleukin (IL)-6, TNF and lymphotoxin (LT)-alpha release from cultured H-RS cells. In addition, CD40L, but not CD30L, induced IL-8 secretion. CD30L and CD40L seem to share some redundant biological activities involved in the deregulated secretion of cytokines known to play a central role in the clinical presentation and pathology of HD. Further, CD30L enhanced surface expression of intercellular adhesion molecule-1 (ICAM-1/CD54) on cultured H-RS cells, which is frequently overexpressed on primary H-RS cells. CD30L- and CD40L-enhanced CD54 surface expression is followed by elevated shedding of CD54, as shown by detection of elevated 82-kDa soluble (s) CD54 levels in culture supernatants after stimulation with both ligands. CD30L and CD40L share common pleiotropic biological activities on CD30+/CD40+ H-RS cells and are elements of the cytokine and cell contact-dependent activation network typical for HD, a tumor of cytokine producing cells.

CD30 Ligand↗

PubMed1995

B-cell stimulation.

Recent studies have identified CD40 ligand (CD40L) as the critical membrane-expressed molecule responsible for T cell dependent B-cell activation. CD40L co-operates with various cytokines to induce B-cell activation, proliferation, and immunoglobulin isotype switching. Some antigens, however, can also stimulate B-cell activation and isotype switching in the absence of CD40L or T cells. Recent studies have suggested that cytokines derived from non-T cells, such as natural killer cells, macrophages and mast cells, are responsible for isotype switching in T cell independent responses.

Animals↗

PubMed1995

CD40 cross-linking inhibits specific antibody production by human B cells.

Ligation of CD40 on B cells is a co-stimulatory signal for proliferation, antibody secretion, heavy chain switching and rescue from apoptosis after somatic mutation in the germinal centre. The importance of these manifold responses to CD40 activation for humoral immunity is exemplified by the inability of boys with X-linked hyper IgM syndrome to make IgG, IgE or IgA due to a mutation in in the gene coding for CD40 ligand (CD40L). In the present study, we have investigated the effect of CD40 ligation on specific antibody production by human B cells to influenza virus. The antibody response was T cell dependent and specific for the strain of influenza virus used as antigen. Addition of either CD40 mAb or recombinant trimeric CD40L profoundly inhibited specific antibody production. Antibody production by unseparated tonsillar mononuclear cells and by T-depleted B cells stimulated with antigen in the presence of T cell replacing factor were equally inhibited with CD40 antibody showing that the effect was due to ligation of CD40 on B cells rather than blocking of T cell help. The specific antibody detected in these experiments was mostly IgG with little or no IgM and was obtained from surface IgM B cells consistent with activation of a secondary (memory) response. Co-stimulation of tonsillar B cells with CD40 antibody and anti-IgG induced proliferation of IgG+ B cells. These results suggest that CD40 ligation can inhibit specific antibody responses and stimulate proliferation in the same IgG+ (memory) B cell subpopulation. Addition of CD40 antibody during the first 24-48 h of the response was required for inhibition, suggesting that the effect was on early B cell activation and/or proliferation required for antibody production. There was no correlation, however, between the ability of CD40 mAb to stimulate proliferation and inhibit antibody production. We suggest that early activation of CD40 in the specific antibody response inhibits the formation of plasma cells and promotes instead the generation of memory cells.

Antibodies, Monoclonal↗

PubMed1995

Molecular characterization of the pan-B cell antigen CDw78 as a MHC class II molecule by direct expression cloning of the transcription factor CIITA.

Antibodies against a pan-B cell-surface marker have been statistically clustered to define the CDw78 antigen. Molecular characterization of the CDw78 antigen was performed to determine its functional role in T and B cell interactions. Screening a direct expression cDNA library, made from the Epstein-Barr virus-transformed, B lymphoblastoid cell line MP-1 with an anti-CDw78 mAb, we have isolated a 3.8 kb cDNA encoding the transcription factor CIITA, previously shown to transactivate human MHC class II expression. Using several anti-CD78 mAb, we observed induced expression of the CDw78 antigen on the surface of monkey CV-1/EBNA cells transfected with the CIITA cDNA clone. Apparently, recombinant human CIITA can regulate the expression of monkey MHC class II which is recognized by anti-human CDw78 mAb. The anti-human CDw78 mAb seem to recognize a monomorphic determinant of MHC class II. Expression of recombinant human MHC class II antigens in CV-1/EBNA cells was recognized by a panel of CDw78 mAb, as well as by anti-human MHC class II mAb. These data show that the CDw78 antigen is expressed as part of the MHC class II molecule and appears similar if not identical to the alpha beta heterodimeric MHC class II antigen.

Amino Acid Sequence↗

PubMed1994

Humoral immune responses in CD40 ligand-deficient mice.

Individuals with X-linked hyper-IgM syndrome fail to express functional CD40 ligand (CD40L) and, as a consequence, are incapable of mounting protective antibody responses to opportunistic bacterial infections. To address the role of CD40L in humoral immunity, we created, through homologous recombination, mice deficient in CD40L expression. These mice exhibited no gross developmental deficiencies or health abnormalities and contained normal percentages of B and T cell subpopulations. CD40L-deficient mice did display selective deficiencies in humoral immunity; basal serum isotype levels were significantly lower than observed in normal mice, and IgE was undetectable. Furthermore, the CD40L-deficient mice failed to mount secondary antigen-specific responses to immunization with a thymus-dependent antigen, trinitrophenol-conjugated keyhole limpet hemocyanin (TNP-KLH). By contrast, the CD40L-deficient mice produced antigen-specific antibody of all isotypes except IgE in response to the thymus-independent antigen, DNP-Ficoll. These results underscore the requirement of CD40L for T cell-dependent antibody responses. Moreover, Ig class switching to isotypes other than IgE can occur in vivo in the absence of CD40L, supporting the notion that alternative B cell signaling pathways regulate responses to thymus-independent antigens.

Animals↗

PubMed1994

The CD39 lymphoid cell activation antigen. Molecular cloning and structural characterization.

CD39, a 70- to 100-kDa molecule expressed primarily on activated lymphoid cells, was previously shown to mediate B cell homotypic adhesion when ligated with a subset of anti-CD39 mAbs. In the present study, we describe the cloning and molecular characterization of human and murine CD39. The nucleotide sequence of human CD39 includes an open reading frame encoding a putative 510 amino acid protein with six potential N-linked glycosylation sites, 11 Cys residues, and two potential transmembrane regions. Murine CD39 shares 75% amino acid sequence identity with human CD39 but fails to cross-react with anti-human CD39 mAbs. Although there were no significant similarities with other mammalian genes, considerable homology was found between CD39 and a guanosine diphosphatase from yeast. A series of mouse-human hybrid molecules was constructed to determine the general topology of CD39 and the location of a biologically functional epitope. These findings and supporting evidence from an anti-CD39 mAb-selected phage peptide display library indicate a likely model wherein a short intracellular N-terminus is followed by a large extracellular loop containing the epitope recognized by stimulatory anti-CD39 mAbs, and a short intracellular C terminus. The results demonstrate that CD39 is a novel cell surface glycoprotein with unusual structural characteristics.

Adenosine Triphosphatases↗

PubMed1994

Expression and function of CD40 on Hodgkin and Reed-Sternberg cells and the possible relevance for Hodgkin's disease.

CD40 was originally described as a B-cell-restricted antigen and was subsequently found to be a member of the tumor necrosis factor (TNF) receptor superfamily. CD40 is also expressed on dendritic cells, thymic epithelium, monocytes, and some carcinoma cell lines, and plays a critical role in cell contact-dependent activation. Primary and cultured Hodgkin and Reed-Sternberg (H-RS) cells, the presumed malignant cells of Hodgkin's disease (HD); were found to express high levels of cell surface CD40. We found that recombinant CD40 ligand (CD40L) induced interleukin-8 (IL-8) secretion and enhanced IL-6, TNF, and lymphotoxin-alpha (LT-alpha/TNF-beta) release from cultured H-RS cells. These cytokines play a significant role in the clinical presentation and pathology of HD, a tumor of cytokine-producing cells. CD40L had no mitogenic activity for HD-derived cell lines. In contrast, CD40L enhanced expression of costimulatory molecules intracellular adhesion molecule-T and B7-1 on cultured H-RS cells, both of which are overexpressed on primary H-RS cells. In addition, CD40L induced a 40% to 60% reduction of the expression of the HD-associated CD30 antigen, another member of the TNF receptor superfamily. Primary and cultured H-RS cells express not only CD30, but also CD40. CD40L has pleiotropic biologic activities on H-RS cells, and the CD40-CD40L interaction might be a critical element in the deregulated cytokine network and cell contact-dependent activation cascade typical for HD.

Adult↗

PubMed1994

CD40 ligand (CD40L) expression and B cell function in agammaglobulinemia with normal or elevated levels of IgM (HIM). Comparison of X-linked, autosomal recessive, and non-X-linked forms of the disease, and obligate carriers.

Hyper-IgM syndrome is a rare immunodeficiency characterized by low or absent IgG, IgA, and IgE with normal or elevated levels of IgM. It can occur as an acquired or familial disorder with either X-linked or autosomal modes of inheritance. The X-linked form (HIGM1) is a result of mutations in the CD40 ligand (CD40L) gene, but the defect in non-X-linked forms of the disease (HIM) has not been determined. We show here that CD40L expression on activated T cells from non-X-linked patients can be detected by CD40Fc, 5c8 Mab, and anti-TRAP, whereas activated T cells from HIGM1 patients either had no detectable CD40L (Type I), or stained with anti-TRAP but not CD40Fc or 5c8 (Type II). Activated T cells from obligate carriers varied from low to normal expression of CD40L. B cells from HIGM1 and non-X-linked HIM patients proliferated in response to CD40L. Costimulation of B cells from HIGM1, from sporadic HIM, or from non-X-linked HIM patients with CD40L plus IL-2 resulted in some IgM production, but no significant IgG or IgA. Costimulation with CD40L plus IL-10 resulted in significant IgG and/or IgA secretion by B cells from some HIGM1 patients, but consistently failed to stimulate IgG or IgA secretion by B cells from non-X-linked patients. In addition, costimulation with CD40L and IL-4 failed to induce IgE secretion by B cells from one non-X-linked HIM patient, and induced a weak response in another. These results suggest that patients with non-X-linked forms of HIM may have an intrinsic B cell defect preventing heavy chain switching, which is not related to expression of CD40L.

Adolescent↗

PubMed1994

Costimulation through CD28 enhances T cell-dependent B cell activation via CD40-CD40L interaction.

Changes in T cell helper function were analyzed when anti-CD3-activated T cells were costimulated with mAbs to the CD28 receptor (anti-CD28). T cell-dependent B cell growth and differentiation were consistently augmented if anti-CD3 stimulated-T cells were simultaneously activated with anti-CD28. Although anti-CD28 enhanced IL-2 and IL-4 production, it did not increase B cell responses solely by augmenting production of soluble lymphokines. Anti-CD28 costimulation induced increases on T cells of CD40 ligand (CD40L), known to promote B cell proliferation and Ig secretion. Because anti-CD28 promoted T cell helper functions and expression of CD40L, we examined the dependence for CD40L during T cell-dependent B cell responses. Although soluble CD40 fusion proteins only partially inhibited T cell-dependent B cell activation, we found a strict requirement for CD40L expression at initiating B cell responses. Both CD40L expression and T cell help were blocked by cyclosporin A after TCR cross-linking, and, unlike T cell proliferation, both remained cyclosporin A sensitive during CD28 costimulation. In addition, anti-CD28 could not compensate for the T cell helper deficiency of hyper IgM syndrome patients who lack functional CD40L. Thus, anti-CD28-induced T cell help is delivered via a CD40L-dependent process. The fact that cross-linking CD40 on B cells promotes expression of the B7/BB-1 ligand for CD28 suggest T and B interactions may have a reciprocal amplification mechanism.

Antigens, CD↗

PubMed1994

Inhibition of human B-cell lymphoma growth by CD40 stimulation.

CD40 is a molecule present on B lymphocyte lineage cells that is important in B-cell differentiation and activation. Signaling through CD40 has been shown to exert costimulatory signals on normal B cells resulting in proliferative and differentiation responses. Examination of several B-cell lymphomas showed cell-surface expression of the CD40 molecule. Incubation of these lymphomas with anti-CD40 antibodies resulted in significant growth inhibition in vitro. Cross-linking of the CD40 antibodies resulted in even greater inhibition of proliferation. A recombinant soluble human CD40 ligand was also shown to inhibit lymphoma proliferation. When various human B-cell lymphomas were transferred into mice with severe combined immune deficiency, the treatment of the mice with anti-CD40 antibodies resulted in significant increases in survival showing that anti-CD40 is efficacious after in vivo administration. Thus, CD40 stimulation by either the antibody or soluble ligand directly inhibits human B-cell lymphoma growth and therefore, may be of significant clinical use in their treatment.

Animals↗

PubMed1994

B cell IL-7. Human B cell lines constitutively secrete IL-7 and express IL-7 receptors.

IL-7 was originally reported as a cytokine produced by stromal cells which supports pre-B cell proliferation in vitro. To determine whether human B cells secrete IL-7 and express IL-7R we studied a wide panel of B cell lines (CLS). In Northern blot analysis we detected 2.4 kb IL-7 mRNA and by quantitative PCR we demonstrated IL-7 expression in 5 of 6 B CLS derived from patients with AIDS-associated Burkitt's lymphoma (AABCL), 3 of 3 CLS derived from patients with American Burkitt's lymphoma and 5 of 6 normal lymphoblastoid CLS. Only 1 of 5 African Burkitt's lymphoma CLS and 2 of 7 EBV- CLS expressed IL-7. A total of 484-bp amplicons was cloned and sequenced and found to correspond to the original IL-7 sequence. Constitutive IL-7 secretion was detected in 5 of 6 AABCL and in 6 of 7 normal lymphoblastoid CLS but in none of the 7 EBV- CLS. IL-7R expression was demonstrated in 8 of 26 CLS, none of which secreted IL-7. Our data suggest that 1) IL-7 mRNA is expressed in malignant B cell phenotypes, which correspond to a narrow window in the B cell differentiation pathway (pre-B, early B, intermediate B), as well as in normal lymphoblastoid B CLS. 2) IL-7 mRNA is expressed in both EBV+ and EBV- CLS, but only the EBV+ CLS secrete IL-7. 3) B cells activated by both EBV and HIV-1 (AABCL) secrete the greatest amount of IL-7. 4) IL-7 autocrine loops are not evident since IL-7R were detected on on CLS, which do not secrete IL-7. Our data provide the first direct evidence of IL-7 secretion by human cells and it is yet to be determined whether IL-7 is secreted by other cell types.

B-Lymphocytes↗