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Biomedical subjects

R G Lynch

Publications and source records attributed to R G Lynch.

At least 55 records · Page 3Linked to original sources
PubMed1993

Lymphocyte Fc receptors: the special case of T cells.

The different cell types of the lymphoid-myeloid lineage constitutively express various Fc receptors. The exception is the T-cell lineage where most subsets express Fc receptors only during a narrow window following cellular activation. M. Sandor and R.G. Lynch summarize information which identifies a multi-level relationship between Fc receptors and clonotypic T-cell receptors and conclude that this relationship might account for the restricted expression of Fc receptors on T cells.

Animals↗
PubMed1993

CD23 isoforms in murine T and B lymphocytes.

A major objective of the present studies was to seek biochemical evidence for the production of the low affinity IgE Fc receptor (CD23) by murine T cells. These studies have established that most of the murine T cell populations analyzed express CD23 mRNA. Some T cell populations contained a transcript whose nucleotide sequence was identical to that previously reported for the CD23 cDNA cloned from murine B cells. Some T and B cells contained CD23 transcripts lacking exon-3-encoded sequences. If translated, these transcripts would yield a CD23 polypeptide lacking the transmembrane segment and all but six amino acids of the intracytoplasmic tail. The truncated CD23 transcripts detected in T and B cells in these studies appear to be generated via alternative splicing. It is possible that these transcripts encode soluble, secretory forms of CD23, or that these transcripts have regulatory functions that influence CD23 gene expression. These investigations provide new information about the structure of murine lymphocyte CD23, they predict the occurrence of CD23 isoforms in the mouse, and they present direct evidence for the production of CD23 by murine T lymphocytes.

Amino Acid Sequence↗
PubMed1992

Ontogeny and distribution of the murine B cell Fc gamma RII.

The distribution and expression of the IgG FcRII (Fc gamma RII) on normal murine B cells was examined. Using multicolor flow cytometry, spleens from neonatal mice of increasing age and adult bone marrow were analyzed for expression of the Fc gamma RII. In addition, B cells from peripheral lymphoid organs, as well as panel of B cell tumors, were tested. The results demonstrate that the Fc gamma RII is expressed on all pre-B cells and immature B cells in the neonatal spleen and adult bone marrow, on all mature B cells in peripheral lymphoid organs, and on switched B cells in Peyer's patches. Furthermore, the Fc gamma RII was found to be present on B cell tumors representative of all stages of B cell maturation and differentiation. Taken together, the results indicate that Fc gamma RII is expressed during the entire lifetime of the B cell. In addition, examination of spleen cells from neonatal mice revealed a large number of pre-B cells, phenotypically defined as B220+, IgM-. These pre-B cells were present at birth, peaked in number between 2 and 3 wk of age, and became a minor population by day 30. Further phenotypic analysis of these cells demonstrated the expression of the BLA-1 and BP-1 Ag, and the lack of T cell and NK cell markers, thus confirming their assignment to the B cell lineage. Finally, the Fc gamma RII present on these pre-B cells was shown to be functional, by virtue of its ability to bind aggregated IgG.

Animals↗
PubMed1992

In vitro and in vivo activation of murine gamma/delta T cells induces the expression of IgA, IgM, and IgG Fc receptors.

The present studies examined resting and activated murine gamma/delta T lymphocytes, in vitro and in vivo, for surface expression of FcR. Polyclonal gamma/delta TCR+ lymphocytes selectively grown from the spleen and intestine of normal mice did not express FcR when the cells were in a resting state, but when cells were activated with anti-CD3 antibody virtually all of the splenic gamma/delta lymphocytes and a large subpopulation of the intestinal gamma/delta lymphocytes expressed IgA and IgM FcR. This was confirmed by using transgenic mice. Resting gamma/delta TCR+ lymphocytes from the spleen, thymus, lymph node, and blood of gamma/delta TCR transgenic mice did not express FcR for any of the five major classes of Ig H chains. Activation of the gamma/delta TCR+ cells via the CD3/TCR complex induced high levels of IgM and IgA FcR and low levels of IgG FcR. Finally, in hepatic granulomas of schistosome-infected mice, activated gamma/delta TCR+ cells are present and express high levels of IgA and IgM FcR and low levels of IgG FcR. These investigations establish that transition of gamma/delta TCR+ lymphocytes from a resting to an activated state (triggered via the T3Ti TCR complex) is accompanied by the induction of surface membrane receptors specific for Ig H chain isotypes. The activation-linked expression of FcR on gamma/delta TCR+ lymphocytes provides potential mechanisms for coupling the functional activities of gamma/delta T lymphocytes with immune mechanisms that involve Ig molecules, such as antibody-dependent cellular cytotoxicity.

Animals↗
PubMed1992

Expression of IgA and IgM Fc receptors on murine T lymphocytes.

Fc receptors are induced on T cells following activation via the TCR. T cells that express Fc receptors transiently have the ability to use two different cognate systems: the TCR and immunoglobulins bound to the Fc receptors. The studies discussed in this article are focused on the Fc alpha and Fc mu receptors that can be induced on certain subsets of murine T lymphocytes. The article emphasizes the role of the T cell receptor for antigen in the expression of Fc alpha and Fc mu receptors on murine T cells and reviews experimental observations that suggest significant molecular heterogeneity of these Fc receptors. The finding that regulation of expression of Fc alpha receptors and Fc mu receptors on T lymphocytes is linked to cellular activation via the CD3/TCR complex implies that these Fc receptors might mediate important functions in the biology and pathology of T cells.

Animals↗
PubMed1991

Immune dysfunction in mice with plasmacytomas. I. Evidence that transforming growth factor-beta contributes to the altered expression of activation receptors on host B lymphocytes.

Plasmacytoma-bearing mice (PC-mice) develop a polyclonal B cell immunodeficiency syndrome characterized by marked impairment of: a) primary antibody responses and b) proliferative responses to B cell mitogens. The present investigations used two-color flow cytometry to examine B lymphocytes from the spleens and lymph nodes of PC-mice and found decreased surface membrane expression of surface IgM (sIgM), transferrin receptors (TfR) and IgE FcR (CD23), increased expression of class II MHC, but normal expression of B220, Mel-14, Fc gamma RII, and Fc mu R. These changes were not related to the H chain class or the amount of Ig produced by the plasmacytoma. When cultured with IL-4, B lymphocytes from PC-mice increased their expression of sIgM and class II MHC, but not of CD23. Several findings implicate transforming growth factor-beta 1 (TGF-beta 1) in the mechanism that modulates receptor expression on B lymphocytes in PC-mice: a) ascites fluid from PC-mice contains large quantities of TGF-beta 1; b) supernatants of cultured spleen cells from PC mice contain up to eightfold more TGF-beta than is found with normal spleen cells; c) cloned plasmacytoma cells produce TGF-beta in vitro; and d) the abnormal phenotype of B cells from PC-mice, i.e., decreased CD23, sIgM, and TfR, and increased class II MHC, is induced on normal B cells cultured in the presence of TGF-beta 1. Because sIgM, TfR, class II MHC, and CD23 are molecules that play fundamental roles in the activation of normal B cells, their modulation by TGF-beta 1: a) identifies molecular mechanisms that could account for some of the known immunosuppressive properties of TGF-beta 1 and b) implicates TGF-beta in the pathogenesis of the polyclonal B cell immunodeficiency that is characteristic of plasma cell tumors.

Animals↗
PubMed1991

Enhancer mediated suppression of epsilon heavy-chain gene expression in a murine IgE-producing hybridoma.

In vitro co-culture of IgE-secreting hybridoma cells (B53) with spleen cells harvested from mice with established B53 tumours results in a specific, T cell-dependent suppression of epsilon-chain expression in the B53 cells. The role of immunoglobulin enhancers in the suppression of IgE synthesis in B53 cells was examined by transfecting B53 cells with CAT expression vectors containing the immunoglobulin heavy- or kappa light-chain intron enhancers or a Rous sarcoma virus (RSV) LTR. When epsilon-chain expression of transfected cells was suppressed in vitro. CAT expression was also suppressed in cells transfected with vectors containing the immunoglobulin heavy-chain gene enhancer, but not in cells transfected with vectors containing the kappa enhancer or RSV LTR. Thus, the T cell-dependent suppression of IgE synthesis in B53 cells correlates with a specific inactivation of the immunoglobulin heavy chain enhancer, strongly suggesting that T cell-mediated suppression of Ig synthesis can normally occur through specific repression of Ig enhancer function. This represents a new regulatory pathway involved in the control of IgE synthesis and is the first indication that the enhancer mediated expression of Ig genes in B cells can be modulated through T cell-dependent processes.

Animals↗
PubMed1991

The expression of B cell surface receptors. III. The murine low-affinity IgE Fc receptor is not expressed on Ly 1 or 'Ly 1-like' B cells.

The distribution of IgE FcR (Fc epsilon R)-positive and -negative B cells was examined in normal adult mice. Using three-color flow cytometry, the expression of the Fc epsilon R was analyzed on various B-cell subsets present in the peritoneum and spleen. The results demonstrate that in the peritoneal cavity, the Fc epsilon R is not expressed on the large majority of Ly 1+ B cells and Ly 1-, Mac 1+ sister B cells. The receptor is present, however, on the small number of conventional B cells residing in the peritoneum. Although interleukin 4 (IL-4) can increase the levels of the Fc epsilon R on conventional B cells, incubation of Ly 1 and sister B cells with IL-4 did not result in the expression of the Fc epsilon R. When examining B cells present in the spleen, a small subset of B cells was consistently found to be Fc epsilon R-. These Fc epsilon R- cells were IgM-bright, IgD-dull and largely Ly 1- and Mac 1-negative. Staining of splenic tissue sections revealed that the Fc epsilon R- B cells were primarily localized to the marginal zones, whereas the Fc epsilon R+ B cells were found in the follicles. Taken together, the results indicate that the Fc epsilon R may be a useful marker in delineating the various B-cell subsets. In the peritoneum, the Fc epsilon R appears to discriminate conventional B cells from those of the Ly 1/sister lineage, and in the spleen it is likely to distinguish resting follicular B cells from Ly 1/sister and marginal zone B cells.

Animals↗
PubMed1990

In vivo and in vitro regulation of IgE production in murine hybridomas.

Normal BALB/c mice injected i.p. with the IgE-secreting hybridomas B53 (epsilon, kappa anti-DNP), SE1.3 (epsilon, kappa, anti-arsonate) or A3B1 (epsilon, kappa, anti-TNP) were monitored for serum IgE concentrations and frequencies of splenic T lymphocytes with surface membrane receptors for the Fc portion of IgE (Fc epsilon R+ T lymphocytes). Mice with B53 or SE1.3 hybridomas initially developed high concentrations of IgE and CD8+ Fc epsilon R+ T lymphocytes, followed by a progressive decline in both serum IgE and expression of cytoplasmic epsilon-chains in the hybridoma cells. Serum IgE concentrations in mice with A3B1 hybridomas progressively increased without development of Fc epsilon R+ T lymphocytes nor a subsequent decline in IgE or change in cytoplasmic epsilon-chain expression in the A3B1 cells. An in vitro system in which the IgE-secreting hybridoma cells were cocultured with spleen cells harvested from mice with established B53 tumors was used to investigate the mechanisms involved in the inhibition of IgE production by the hybridoma cells. The results of these studies indicate that: 1) the induction/upregulation of Fc epsilon R on CD8+ T lymphocytes in vivo requires factors in addition to high serum IgE concentrations; 2) in addition to CD8+ Fc epsilon R+ T lymphocytes and monocytes, another, as yet unidentified, splenic cell component appears to contribute to the process by which epsilon-chain expression in IgE-secreting hybridoma cells is suppressed, and 3) a hybridoma (A3B1) that fails to induce CD8+, Fc epsilon R+ T lymphocytes in vivo and is not inhibited in IgE expression in vivo, nonetheless is inhibited in IgE expression in vitro when cocultured with spleen cells from mice with B53 tumors.

Animals↗
PubMed1990

IgA-induced avidity maturation of IgA Fc receptors on murine T lymphocytes.

The analysis of 30 well characterized murine T lymphocyte populations using a cytofluorometric IgA binding assay has identified many populations that are constitutive and/or inducible for IgA receptor expression, and has identified two distinct mechanisms by which IgA up-regulates the IgA-binding properties of murine T cells. Studies with lymphomas, hybridomas, Ag-specific clones and activated normal splenic T cells identified many examples of CD4 and CD8 lineage cells that constitutively expressed IgA receptors. T cell populations that constitutively expressed IgA receptors exhibited enhanced IgA binding after incubation with oligomeric IgA for 18 h. The IgA-induced up-regulation of IgA binding resulted from two distinct processes: 1) an increase in the number of surface membrane IgA binding sites and 2) an increase in the avidity of IgA binding without a change in the number of binding sites. The IgA-induced avidity increase was reflected by a 5- to 10-fold decrease in the apparent Kd. Depending on the T cell population examined the enhanced binding of IgA involved one or both of these mechanisms. T cell populations that did not constitutively express IgA receptors failed to bind IgA after prolonged incubation with oligomeric IgA suggesting that if such cells can express IgA receptors they require other signals to induce their expression. Consistent with this possibility is the finding that resting splenic T cells did not bind IgA but their activation with Con A or mAb anti-T3 resulted in high level expression of IgA receptors. These studies have identified multiple distinct mechanisms that alter the IgA-binding properties of murine T cells and are discussed in terms of their possible physiologic significance.

Animals↗
PubMed1990

CD4+ murine T cell clones that express high levels of immunoglobulin binding belong to the interleukin 4-producing T helper cell type 2 subset.

A panel of 20 murine CD4+ clones was examined for the presence of surface membrane receptors for IgA, IgM, IgD, IgE, and IgG. High level expression of multiple Fc receptors (FcRs) was found on all Th2 clones. FcR expression was low or undetected on the Th1 clones. The preferential expression of FcR on activated Th2 cells suggests potential mechanisms for immunoregulatory interactions with B cells.

Animals↗
PubMed1989

Expression of B cell surface receptors. II. IL-4 can accelerate the developmental expression of the murine B cell IgE Fc receptor.

The ability of IL-4 to influence the developmental expression of the murine B cell IgE Fc receptor (Fc epsilon R) was examined. Spleen cells from neonatal mice of increasing age were incubated overnight with IL-4 and subsequently examined with multicolor flow cytometry. The results demonstrate that IL-4 can significantly increase the number of maturing B cells which express the Fc epsilon R. This effect was only seen however, on those neonatal B cells which already displayed surface IgD. Splenic B cells which were IgM+, IgD- failed to express the Fc epsilon R when treated with IL-4, even though they responded by increasing their level of class II Ag expression. Further experiments showed that the inability of IgD- immature B cells to express the Fc epsilon R could not be entirely explained by their assignment to the Ly-1 lineage. Taken together, these results indicate that IL-4 can accelerate the developmental expression of the B cell Fc epsilon R, but only on those B cells that are mature enough to express IgD.

Animals↗
PubMed1988

Characterization of the murine T cell receptor for IgE (Fc epsilon RII). Demonstration of shared and unshared epitopes with the B cell Fc epsilon RII.

Antigenic relationships between the low affinity Fc epsilon R present on murine B and T lymphocytes were studied. A rat mAb (B3B4) and two polyclonal antisera produced by immunizing with the murine B lymphocyte Fc epsilon RII were examined for their ability to inhibit binding of IgE to murine B or T lymphocytes, using an IgE-specific rosette assay. One polyclonal antiserum (goat-anti-mouse Fc epsilon R) inhibited binding of IgE to both B and T lymphocytes, whereas another polyclonal antiserum (rabbit-anti-mouse Fc epsilon R) and the rat mAb inhibited the binding of IgE to B lymphocytes but did not influence the binding of IgE to T lymphocytes. When lymphocytes were surface labeled with 125I, 49-kDa and 38-kDa IgE-binding proteins were immunoprecipitated from B lymphocyte lysates by B3B4 and from B and T lymphocyte lysates by the goat antiserum. Taken together, these results suggest that the Fc epsilon R present on murine B and T lymphocytes are structurally related receptors that share some, but not all, epitopes.

Animals↗
PubMed1988

Expression, distribution and specificity of Fc receptors for IgM on murine B cells.

Subpopulations of normal adult murine splenic B cells and a panel of murine B cell tumors were examined for their ability to bind murine IgM specifically. By using two-color flow cytometric analyses, we have demonstrated that 90 to 95% of surface (s)IgD+ B cells express surface membrane receptors for IgM (Fc mu R). The binding of pentameric murine IgM to splenocyte Fc mu R was IgM-specific since it was totally inhibited by other polymeric IgM proteins, but not by Ig of other H chain classes or by mAb specific for the murine IgG or IgE FcR. Binding of IgM to splenic cells was saturable. Fc mu R were co-expressed with the Fc gamma R as well as the Fc epsilon R on the majority of splenic B cells. Minor populations of splenic mononuclear cells expressed only an Fc mu R, Fc gamma R or Fc epsilon R. In a survey of B tumor cell lines representing different stages of B cell development, we observed that the Fc mu R was expressed on pre-B cell lines and that Fc mu R detection was maximal on immature B cell lines that expressed sIgM and low amounts of sIgD and Ia. Fc mu R were not detected on cell lines that had switched from sIgM to the expression of another sIg, or on plasmacytomas and hybridomas. The studies with normal splenocytes establish that the majority of sIgD+ B lymphocytes in adult BALB/c mice express surface membrane receptors that specifically bind IgM. The studies with B lineage tumor cells suggest that the expression of Fc mu R on B cells is developmentally regulated and that the pattern of expression exhibited by Fc mu R during B cell ontogeny differs from the patterns that have been previously found for IgG and IgE FcR. These observations raise the possibility that Fc mu R might have a functional significance in some aspect of B cell maturation and activation. By using a family of IgM H chain constant region domain deletional mutants, we have further demonstrated that, like the T cell Fc mu R, the B cell Fc mu R also requires a C mu 3 domain for binding to occur, raising the possibility that the T and B cell Fc mu R in mice may be structurally related molecules.

Animals↗
PubMed1988

The expression of B cell surface receptors. I. The ontogeny and distribution of the murine B cell IgE Fc receptor.

The ontogenic appearance and lymphoid tissue distribution of the murine B cell IgE FcR (Fc epsilon R) was examined. Flow cytometry was utilized to study the expression of the Fc epsilon R on splenic B cells from mice of increasing age, as well as B cells from various lymphoid organs. A large panel of B cell tumors was also screened for the presence of the Fc epsilon R. The results demonstrate that the Fc epsilon R appears very late in B cell development, and is preceded in appearance even by IgD. In adult animals, the Fc epsilon R was found to be expressed on virtually all mature IgM, IgD bearing B cells, whether taken from the spleen, lymph nodes, or Peyer's patches. Further examination showed that B cells which had switched to express an isotype other than IgD, appeared to no longer display the Fc epsilon R. When surveying a variety of B cell tumors, the Fc epsilon R was found to be present on WEHI 279, an IgM, IgD-bearing lymphoma. The receptor was not found on pre-B cell, immature B cell, switched B cell, or secreting B cell tumors. Taken together, these results indicate that the B cell Fc epsilon R is expressed predominantly on mature, virgin B cells, and is lost after activation and switching.

Animals↗