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Biomedical subjects

R B Corley

Publications and source records attributed to R B Corley.

At least 55 records · Page 3Linked to original sources
PubMed1986

Inducible lymphokines of T cell tumors.

T lymphocytes comprise a major class of lymphocytes and are themselves functionally heterogeneous. Some T lymphocyte functions are mediated by soluble products called lymphokines. Different lymphokines promote the activation, growth and differentiation of T and B lymphocytes, macrophages, and hemopoietic cells. Lymphokine production is associated with, but not limited to, helper T cells, and usually follows antigenic or mitogenic stimulation. The recognition that some lymphokines are produced after stimulation of neoplastic T cells has proved advantageous in the study of these molecules. T cell tumors are monoclonal, grow easily in vitro, and may produce fewer lymphokines than normal T cells. Thus, the purification and biochemical and biological characterization of some lymphokines have been facilitated by the availability of these tumors. More recently, T cell tumors have been used for evaluating the molecular structure of lymphokine-encoding genes. They have also provided information relevant to our understanding of the nature of T cell neoplasia.

Animals↗
PubMed1985

Antigen-nonspecific T cell-derived factors in B cell activation: differences in the requirements for interleukin 2 in responses of unprimed and primed B cells.

The requirements for interleukin 2 (IL2) and other T cell-derived helper factors in the responses of unprimed and antigen-primed B cells to sheep erythrocytes were investigated. Unprimed B cells required both IL2 and additional factor(s), hereafter referred to as T cell-replacing factor (TRF), in addition to specific antigen, for antibody production. IL2 was required only during the early stages (approximately equal to 24 h) of culture while TRF was necessary only after this time and was then required throughout the remaining culture period. IL2 stimulated the appearance of Thy-1+ cells in unprimed "B cell" populations which could substitute for the function of IL2, implicating an indirect role, at least in part, for IL2 in the TRF assay. Furthermore, in contrast to the results with unprimed B cells, primed B cells required only late-acting TRF for optimal antibody responses. We suggest that IL2 activates residual T cells or precursors of T cells in B cell populations which then function, in the presence of specific antigen, to render B cells receptive to T cell-derived factors which promote B cell growth and differentiation.

Animals↗
PubMed1985

Three classes of signalling molecules on B-cell membranes.

The question of whether surface immunoglobulin and Ia molecules have a signalling function in helper T cell-dependent activation of B cells has been evaluated. Two sources of B cells have been used, one a purified population of hapten-binding B cells, the other a B-cell lymphoma, CH12, with known antigen specificity. Evidence is presented that both immunoglobulin and Ia molecules are receptors actively involved in the initial activation of resting B cells. Nevertheless, the requirements for ligand binding to either receptor can be bypassed under appropriate conditions, and the implications of this result for the function of these molecules is discussed. With respect to B-cell Ia, the authors present data that demonstrate two distinct functions of this molecule, one as a restricting element for T-cell activation, the second as a signalling receptor for B-cell excitation. On the CH12 surface, the I-A molecule fulfills the former function, but T-cell interactions with I-A fail to result in B-cell stimulation, suggesting that B-cell Ia may limit helper T cell-B cell interactions. We suggest that the binding of antigen surface immunoglobulin and binding of helper T-cell receptors to the appropriate Ia molecule(s) results in the activation of genes that encode for a third class of membrane B-cell receptors, those that bind B-cell stimulating factors.

Animals↗
PubMed1985

Two separate functions of class II (Ia) molecules: T-cell stimulation and B-cell excitation.

We have evaluated the role of major histocompatibility complex-encoded class II (Ia) molecules as transmembrane signaling receptors in the T helper cell-dependent activation of B lymphocytes. For these studies, we utilized the murine B-cell lymphoma CH12, which expresses both I-A and I-E class II molecules. In addition, CH12 cells carry IgM of known antigen specificity and require both specific antigen and Ia-restricted T-cell help for the induction of antibody secretion. In this respect, they resemble normal resting B cells. We have studied the ability of antigen-specific or alloreactive T helper cells reactive with either the I-A or the I-E molecules on CH12 to be activated and their ability to stimulate antibody production by CH12. The results show that, although CH12 cells present antigen to T helper cells that interact with either the I-A or the I-E molecules, CH12 cells are stimulated to secrete antibody only by T helper cells reactive with their I-E molecules. Our data demonstrate that class II molecules are transducers of signals for B-cell excitation in addition to serving a restricting function for helper T-cell stimulation. Moreover, the data demonstrate that these two functions, T-cell stimulation and B-cell excitation, are discrete and need not be expressed by the same Ia molecule.

Animals↗
PubMed1984

Regulation of B cell lymphomagenesis by a malignant Qal+ inducer T cell clone.

A series of Thy-1.2+ Ly-1+ Qa-1+ malignant T cell clones have been isolated from murine sarcoma virus-murine leukemia-Moloney (MSV-MuLV-M)-induced B cell lymphomas or from MSV-MuLV-M-infected B6 mice. These T cell clones enhance both antigen-independent and -dependent lymphocyte differentiation and function. They also induce the differentiation of granulocytes and erythrocytes in the stem cell compartment, a function that parallels the immunopathology of the disease in vivo. The malignant T cell appears to sustain B lymphoma growth in vivo by releasing a factor (BCGF) that promotes B cell proliferation.

Animals↗
PubMed1984

Major histocompatibility complex-restricted and unrestricted interactions in the T cell-dependent activation of hapten-binding B cells.

The requirements for linked recognition and major histocompatibility complex-restricted interactions in helper T cell-dependent activation of purified unprimed and primed hapten-binding B cells have been investigated. The activation of unprimed hapten-binding B cells required specific antigen and restricted interactions between helper T cells and B cells. As expected, specific hapten-carrier conjugates were essential for the activation of B cells at low antigen doses. Interestingly, however, supraoptimal concentrations (125 micrograms/ml) of carrier protein alone could substitute for specific conjugates in the activation of unprimed B cells. The requirement for restricted helper T cell-B interactions was unchanged under these conditions. These results are discussed in terms of the signalling requirements for B cell activation. In contrast to the results using hapten-specific B cells from unprimed mice, the further stimulation of B cells prepared from mice primed 5 to 7 days earlier with immunogenic forms of the hapten was limited only by the requirements for helper T cell activation. The transition in the activation properties of B cells following in vivo stimulation was not solely a result of the binding of B cell membrane immunoglobulin to specific antigen, since the interaction of unprimed B cells with hapten during their purification, even for extended periods of time, did not alter the requirements for their further stimulation. These results demonstrate that the recent antigenic experience of B cells determines their activation state which, in turn, dictates the further requirements for helper T cell function in B cell stimulation. This implies that specificity of the immune response is determined in the early stages of B cell activation.

Animals↗
PubMed1984

Role of cell surface immunoglobulin in B-lymphocyte activation.

The role of cell surface immunoglobulin in helper T-cell-dependent B-cell activation was analyzed using a B-cell lymphoma, CH12, with known antigen specificity and activation properties similar to those of a resting B cell. Two sources of helper T cells were used, both selected such that they interact with H-2-encoded determinants on CH12 in the absence of the specific B-cell antigen, sheep erythrocytes. By this dissociation of the specificity of the T cells from that of the B cells, the requirement for antigen in the induction of CH12 to antibody secretion could be studied. The results show that both helper T-cell-B-cell interactions and surface immunoglobulin-antigen binding are involved in inducing B-cell differentiation, thus establishing a signalling function for the antigen receptor on B lymphocytes. Our data also show that the requirement for surface immunoglobulin-ligand interactions in B-cell activation can, under certain conditions, be circumvented, notably when high (nonphysiologic) multiplicities of T-cell help are used.

Animals↗
PubMed1984

Induced differentiation of a B cell lymphoma with known antigen specificity.

We have previously described a murine B-cell lymphoma, CH12, the cells of which bear surface IgM reactive with sheep erythrocytes (SRbc) and which could differentiate to secrete hemolytic antibody. The question addressed in this paper was whether differentiation of CH12 cells could be influenced by interaction with regulatory T cells and antigen. If so, we wanted to know whether the conditions required differed from those known to govern similar interactions with normal B cells. We had two reasons for wanting to answer these questions. First, we wondered whether CH12 could be used as a clonal population of indicator cells to study the regulation of B cell differentiation and, second, we wanted to know the extent to which these neoplastic cells were still responsive to normal regulatory signals. The first addresses a major difficulty which must be faced in studies of normal B cell differentiation: to what extent is the interpretation limited by heterogeneity of the B cells used? The second relates to the nature of neoplasia and the possibility that neoplastic cells might be rendered harmless by inducing terminal differentiation. CH12 is one of a series of transplantable B cell lymphomas which arose in B10.H-2aH-4b p/Wts (2a4b) mice, following intense immunization with SRbc. It is a monoclonal tumor, all the cells of which bear membrane IgM(kappa) of a single idiotype, reactive with sheep and chicken Rbc and with bromelain-treated autologous mouse Rbc. The cells express KkAkEk and Dd antigens appropriate to the H-2a haplotype. During the latter stages of growth in vivo or in vitro, a small proportion (less than 3%) of the cells differentiate to secrete hemolytic antibody as measured by the Cunningham assay for plaque forming cells (PFC). We cultured CH12 cells for 3 or 4 days, together with antigen and spleen cells from primed animals, and assayed for PFC induction. Differentiation was induced by spleen cells from SRbc primed 2a4b mice in the presence of SRbc or ChRbc but not rabbit or human erythrocytes. Activity was depleted by treatment of the spleen cells with anti-Thy-1 or anti-Lyt-1 but not anti-Lyt-2 plus complement. Helper cells could also be induced by priming 2a4b mice with ChRbc but not rabbit or human Rbc. Neither of these last two would induce differentiation of CH12, even when both homologous antigen and SRbc were present in the cultures.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1983

T cell help in cytotoxic T lymphocyte responses. Role of the I region in helper cell induction.

We have studied the in vivo induction of T helper (TH) cells that participate in the generation of cytotoxic T (TC) lymphocytes. Helper activity was measured by the ability of the cells to help resting thymic TC cell precursors develop into effector TC cells in vitro. Direct injection of allogeneic spleen cells into the footpads of mice led to the generation of alloantigen-specific helper cells in the draining popliteal lymph nodes within 4 to 6 days. Helper activity was mediated by nylon-wool-nonadherent Lyt-1+ T lymphocytes; some activity was associated with Lyt-1,2+ cells. The genetic requirements for both the induction and restimulation of C3H anti-H-2d TH cells were investigated using cells from H-2k/H-2d recombinant mice as in vivo immunogens and in vitro stimulators. Evidence is presented that shows in a direct assay that TH cells themselves are specific for I region-coded determinants. Thus, disparity at the left side of the H-2 complex (K to I-E) but not at H-2K alone was necessary and sufficient to induce and reactivate TH cells. Proliferation in mixed lymphocyte culture was measured in combinations in which TH cells were not detectable, supporting the idea that proliferation cannot be strictly considered a measurement of helper cells.

Animals↗
PubMed1982

Recruitment of functional subpopulations of T lymphocytes. Initiator T lymphocytes recruit helper T cells for cytotoxic response.

Initiator T (Ti) lymphocytes are defined by their ability to recruit other T cell populations in vivo. In this study the function of T cells recruited into draining lymph nodes following injection of Ti cells primed to alloantigens in mixed lymphocyte culture was examined. The results demonstrate that alloantigen-specific helper T cells that interact with cytotoxic T (Tc) lymphocyte precursors are recruited, as shown by the significantly higher frequencies of helper cells in draining lymph nodes compared with controls. However, neither Tc cells nor their precursors are recruited. Recruitment by Ti lymphocytes is therefore selective for certain T cell subsets. Proposals to explain the mechanism, specificity, and selectivity of recruitment are discussed. We suggest that Ti cells have a central role in both the initiation of T cell-dependent immune responses and in the maintenance of immunologic memory. Their function is the rapid mobilization of T cell subclasses to a regional lymphoid organ where the immune response subsequently develops.

Animals↗
PubMed1982

The regulation of T cell growth: requirements for the activation and replication of antigen-specific interleukin 2 producing T cells.

The antigenic requirements for stimulating the production of interleukin 2 (IL2) and the growth of IL2 producing T cells was evaluated using antigen-(Keyhole limpet hemocyanin) specific F1 T helper cell lines. The results demonstrate that both the induction and growth of these cells requires specific antigen and antigen-presenting cells of the correct I-A type. Evidence is presented that argues that soluble macrophage derived factors released as a result of T cell-macrophage interaction are insufficient, even in the presence of antigen, to promote growth of IL2 producing cells. We thus conclude that the direct interaction of IL2 producing cells with an antigen presenting cell is obligatory for activation and growth. These results suggest that T cell proliferation, and as a consequence the magnitude of T cell mediated immune responses, is limited by the availability of "approximately" presented antigen to IL2 producing T cells. The requirement for antigen presenting cells in antigen-driven responses is in contrast with mitogen-induced T cell activation, in which soluble factors can substitute for the accessory cells.

Animals↗
PubMed1982

Effect of recent antigen exposure on the functional expression of B cell subpopulations.

We investigated whether the definition of functional B cell subpopulations changes after the exposure of B cells to specific antigen. Recent in vivo priming with fluorescein- (FL) coupled T-independent (TI) antigens leads to an augmentation of the subsequent in vitro responses of B cells to FL-coupled TI antigens, including FL-polymerized flagellin, FL-lipopolysaccharide, and FL-Brucella abortus, as well as a FL-coupled T-dependent (TD) antigen, FL-keyhole limpet hemocyanin (KLH). This effect, which is evident 7 days after priming, is of short duration in that B cells from FL-Ficoll injected mice display normal responsiveness 3 wk after priming. When mice are primed with FL-KLH, the TD antigen, B cells responsive to a subsequent FL-KLH challenge are expanded, but not short-term cross-priming for any of the TI antigen challenges is observed. Limiting dilution precursor analysis shows that B cell populations responding to different FL-coupled TD and TI antigens overlap in unimmunized animals. FL-TI antigen priming induces not only quantitative changes in the responding B cells (increased precursor frequencies) but also results in functional changes in FL-specific B cells. The primed B cells now respond to FL-hapten in a carrier-restricted manner and behave as independent (non-overlapping) subpopulations. We suggest that B cell responses to different forms of the same hapten are influenced in part by their recent "history" of antigenic exposure.

Animals↗
PubMed1981

The effect of second signals on the induction of B cell tolerance: failure of helper T cells to block tolerance induction.

The effect of carrier-primed helper T (Th) cells and T cell-replacing factors on the induction of hapten-specific tolerance in B cells from adult mice has been tested. The 2,4,6-trinitrophenyl conjugate of human gamma-globulin (TNP17HGG) was used as tolerogen in an in vitro tolerance induction system. Tolerance was assessed by the subsequent induction of plaque-forming cell responses using TNP-Brucella abortus and trinitrophenylated sheep red blood cells (TNP-SRBC) plus SRBC-primed Th cells as T-independent (TI) and T-dependent (TD) forms of TNP, respectively. B cells that respond to the different forms of TNP appear to be distinct B cell subpopulations. TNP17HGG induced TNP-specific tolerance in B cells responsive to TI and TD forms of the antigen, although more tolerogen was required to induce unresponsiveness in the TD antigen-reactive B cells. The presence of antigen nonspecific T cell-replacing factors during tolerance induction had no effect on the induction of unresponsiveness in either TI or TD antigen-responsive B cells, although these factors were able to support primary anti-TNP responses in T-depleted B cell populations to subtolerogenic doses of TNP-HGG. Populations of irradiated lymphocytes enriched for HGG-specific Th cells also had no effect on tolerogenesis in TI or TD antigen-responsive B cells, although priming of TD antigen-responsive B cells occurred at subtolerogenic doses of tolerogen. The inability of these Th cells to modulate B cell unresponsiveness was not due to their inability to exert helper function at higher concentrations of HGG. Thus, in this system, tolerance susceptibility is an intrinsic property of B lymphocytes, i.e. immunogenicity vs. tolerogenicity of signals is not determined by a "second signal" provided by Th cells.

Animals↗
PubMed1981

Identification of a brain theta-positive, secretory cell from hematopoietic tissues.

We have characterized a population of large, brain-theta antigen-positive, secretory cells that occur in high frequency among murine bone marrow (approximately 6%), spleen (approximately 0.5%), and fetal liver (approximately 5%) cell populations. They do not occur in significant numbers among lymph node, thymus, and peritoneal exudate cells. These cells are Ly1, Ly2, and Thy1.2 negative, adherent to nylon wool, Sephadex G-10, and plastic, but peroxidase and Sudan black negative. They are radiation, cyclophosphamide, and cortisone resistant. These cells secrete a product of 30,000 to 40,000 m.w. of unknown function. Production of antisera specific for this molecule has facilitated identification of the cell by using a reverse hemolytic plaque-forming cell assay. Possible functions of this cell and its product are discussed.

Animals↗
PubMed1980

Multiple pathways of T-T interaction in the generation of cytotoxic T lymphocytes to alloantigens.

The interaction of T helper (Th) cells with syngeneic and allogeneic cytotoxic T lymphocyte precursors (CTL.P) has been investigated. Unprimed and mixed lymphocyte culture-primed peripheral T cells were used as a source of Th. Thymocytes, which depend upon exogenous Th cells for activation, were used as a source of cytotoxic precursors. Data is presented that demonstrates that at least two pathways of T-T interaction can lead to the activation of cytotoxic lymphocytes. The first is an allogeneic effect, in which Th cells recognize and respond to alloantigens expressed on CTL.P. The second is the interaction of Th cells with syngeneic CTL.P, in which both cell types are thought to respond to alloantigens on stimulator cells. The latter interaction can be shown to be restricted by H-2-linked determinants when primed Th cells are used and allogeneic effects against thymocytes are minimized. Restricted interactions between unprimed Th cells and thymocyte CTL.P have never been observed. Mechanisms that may explain the difference between the interaction of unprimed and primed Th cells with CTL.P are discussed.

Animals↗
PubMed1980

Limiting dilution analysis of the suppressive effect mediated by alloantigen-primed cells.

T cells primed in mixed lymphocyte culture exert both positive and negative allogeneic effects on B cells expressing the appropriate alloantigens. The positive and negative effects can be separated by limiting dilution analysis: positive effects, measured by production of anti-sheep erythrocyte antibody, are revealed when low numbers of primed T cells are added to cultures of B cells and sheep erythrocytes, while suppression of the response occurs at higher T-cell inputs. In the present report, these negative allogeneic effects have been analysed in detail. Suppression was qualitatively and quantitatively similar when helper T cell activity was provided from any of several sources. Helper T cells in the alloantigen-primed population gave rise to active T-cell replacing factors even under conditions in which all microcultures were suppressed and suppressor cells were present at a high multiplicity in every well. The degree of suppression was influenced by the multiplicity of B cells in culture; as the number of B cells increased, more suppressor cells were required to inactivate a microculture. Taken together, these data indicate that the targets of the suppressor cells are B cells and not helper T cells or T-cell replacing factors. Although suppressor cells can prevent the activation of B cells by the more frequent helper cells in the primed T-cell population, detailed analysis of the stoichiometry of the suppression demonstrated that a single suppressor cell is capable of inactivating only a limited number of B cells, suggesting that a 'ratio-dominance' model of suppression is operative in this system.

Animals↗
PubMed1980

Ratio-dominance model of suppression: an analysis by limiting dilution.

A theoretical framework is presented which explores two models of suppressor cell-target cell interactions in T-dependent antibody responses. The first is the full-dominance model, in which a single or limited number of suppressor cells can entirely suppress an immune response irrespective of the multiplicity of other effector cells present. The second is the ratio-dominance model, in which a suppressor cell is capable of inactivating only a certain number of target cells. Thus, the multiplicity of target cells in a given microculture well influences the degree of suppression. Both models are evaluated using limiting dilution analysis and two systems are explored. In the first model, suppressor cells alone are titrated into microculture wells containing all other cells required for an immune response. In the second, suppressor cells are added from populations containing a mixture of helper T cells as well as suppressor cells. This latter type of analysis is similar to that in which populations of T cells primed to alloantigens in mixed lymphocyte cultures are analysed for positive (help) and negative (suppression) allogeneic effects. The analysis allows us to conclude that such suppressor cells operate via a mechanism best described by a ratio-dominance model.

Antibody Formation↗