Separate Signals for the Initiation of Proliferation and Differentiation in the B Cell Response to Antigen

Dutton, Richard

doi:10.1111/j.1600-065x.1975.tb00149.x

Cited by 54 publications

(48 citation statements)

References 39 publications

(28 reference statements)

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“…However, this factor was not able to induce differentiation in preactivated B cells. This finding correlated with earlier studies by ourselves and others that showed Ig production by B cells to be dependent on a sequential presentation of an activation signal, growth factor, and differentiation factor (13)(14)(15).…”

supporting

confidence: 92%

Development of a human T-cell hybridoma secreting separate B-cell growth and differentiation factors.

Butler¹,

Falkoff²,

Fauci³

1984

Proc. Natl. Acad. Sci. U.S.A.

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A cloned human T-cell hybridoma (7D5) secreting B-cell growth factor (BCGF) and B-cell differentiation factor (BCDF) was established. Supernatant from this hybrid was capable of maintaining proliferation in anti-IgM-activated normal human B cells. In addition, the hybridoma supernatant induced differentiation and antibody secretion in Staphylococcus aureus Cowan I-stimulated B cells. No interleukin 2 was present in supernatant from this hybridoma. Molecular size of the hybridoma-derived BCGF and BCDF was determined by gel filtration chromatography. BCGF activity was present in the 20-kDa fractions, and BCDF activity eluted in the 30-to 35-kDa fractions. The isoelectric points of the factors, determined by chromatofocusing, were 6.6 for BCGF and 5.9 for BCDF. Finally, absorption experiments were performed using specific target cells. Phytohemagglutinin-stimulated T-cell blasts did not remove either BCGF or BCDF activity. Anti-IgM-activated B cells absorbed BCGF but not BCDF. In contrast, CESS cells removed BCDF but not BCGF. Thus, a human T-cell hybridoma secreting two distinct B-cell lymphokines was developed. Further immunochemical and functional studies of these immunoregulatory molecules should greatly enhance our understanding of the regulation of human B-cell function in normal and disease states.The production and characterization of immunoregulatory factors acting on B lymphocytes has been an area of recent interest and investigation (1-6). The technology of cloning and hybridization of human and murine T cells has provided renewable sources of monoclonal B-cell-specific lymphokines (7-10). These factors have proven to be powerful tools in delineating the complex mechanisms involved in the regulation of human immune responses.In a previous report, we described the development of a human T-cell hybridoma (2B11) secreting monoclonal B-cell growth factor (BCGF) (11). The hybridoma supernatant was devoid of both interleukin 2 (IL-2) and B-cell differentiation factor (BCDF) activities. The hybridoma-derived BCGF was capable of maintaining proliferation in normal and human B cells that had been activated by Staphylococcus aureus Cowan strain I (SAC) or anti-Ig (12). However, this factor was not able to induce differentiation in preactivated B cells. This finding correlated with earlier studies by ourselves and others that showed Ig production by B cells to be dependent on a sequential presentation of an activation signal, growth factor, and differentiation factor (13-15).In the present study, we report the development of a human T-cell hybridoma secreting BCGF and BCDF Hybridization. T-cell hybridomas were established as described (11). Normal T cells were obtained from human peripheral blood lymphocytes and stimulated with mitogen as described above. These activated T cells were fused with CEM-6 cells (an azaguanine-resistant mutant of human Tlymphoblastoid origin) in a 2:1 ratio in the presence of polyethylene glycol and were suspended in 96-well, flat-bottomed microtiter plates (Costar 3596). Hybri...

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supporting

confidence: 92%

Development of a human T-cell hybridoma secreting separate B-cell growth and differentiation factors.

Butler¹,

Falkoff²,

Fauci³

1984

Proc. Natl. Acad. Sci. U.S.A.

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“…There are many reports indicating that various factors produced by T cells, either after contact with a specific antigen or after stimulation by allogenic cells or mitogens, can replace the requirements for T cells in antibody formation (20)(21)(22)(23). These factors may or may not have antigen specificity and in many instances have been shown to act across an allogenic or even xenogenic histocompatibility barrier (24,25, and Estroff, T. W. and P. Galanaud, personal communication).…”

Section: Discussionmentioning

confidence: 99%

Induction of an antibody response in cultures of human peripheral blood lymphocytes.

Luzzati¹,

Taussig²,

Meo³

et al. 1976

The Journal of Experimental Medicine

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For many obvious reasons the blood represents a more advantageous source of lymphocytes than any surgical material. However, few reports exist of an antibody response in vitro to SRBC with PBL (6, 7), in some instances (8) dependent on a prior stimulation with allogeneic blood lymphocytes. In an attempt to stimulate these cells in vitro to respond to SRBC we met with a number of failures.Having previously observed in rabbits some peculiar features when inducing antibody responses in vitro with blood lymphocytes (9-11), we decided to investigate extensively and systematically the conditions necessary to elicit a good and reproducible antibody response in vitro with human PBL.In this paper we present evidence that, under appropriate conditions, human PBL depleted of an adherent inhibitor cell can be triggered to give a small antibody response. The magnitude of this response is highly increased by an antigen-specific mouse T-cell factor. Materials and Methods Preparation of Peripheral Blood

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“…Nonspecific stimuli, such as mitogens, lectins, antibodies against cell surface proteins, and activating or inhibiting factors from other cells, may well influence the level of "irritability" of the responding cell, making it more or less likely to respond to a given amount of immunogenic signal or even to respond in the absence of specific signals. Factors from T cells (26,27) and macrophages (28,29) Immunology: Dintzis et aPS regulation of the immune response by networks of suppressor and helper cells operating through idiotype-anti-idiotype networks (31,32). Our experimental data suggest that it is not necessary to invoke either ofthese phenomena to explain the early and rapid response to a T cell-independent antigen, Dnp-polyacrylamide.…”

Section: Hown In Figsmentioning

confidence: 99%

Specific cellular stimulation in the primary immune response: experimental test of a quantized model.

Dintzis¹,

Vogelstein²,

Dintzis³

1982

Proc. Natl. Acad. Sci. U.S.A.

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Dose-response and dose-suppression curves have been measured for the primary immune response in mice, in vivo and in vitro, by using size-fractionated linear polymers of acrylamide substituted with hapten. The results are in general agreement with a simple theory based on the premise that the specific primary immunological response is quantized at some fundamental and limiting step, requiring a minimum number of linked antigen receptors for response.The immune response to most antigens is a very complex phenomenon that has resisted quantitative analysis. Some of this complexity may be related to the molecular complexity of many of the antigens (e.g., proteins, cell walls, etc.) which have been used. A relatively simple and specific primary immune response occurs against antigens that are linear polymers of only a few types ofchemical subunits (1-3). These antigens give rise to a rapid primary immune response with the production ofspecific antibody molecules predominantly of the class IgM (4, 5). The immune response to these antigens may be relatively simple because of its rapidity and the apparent minimum involvement of thymus-derived lymphocytes (T cells). Although complex interactions involving suppressor cells, helper cells, and idiotypes seem to be important in more mature, T cell-dependent responses, it is likely, as discussed here, that they are not a dominant factor in the very early and rapid T cell-independent responses.It long has been observed that multivalent antigens are better immunogens than are monovalent ones; indeed, a number of investigators have proposed that triggering of immunocompetent cells (B cells) to form antibody requires adequate crosslinking of surface receptors by multivalent ligands (6)(7)(8)(9)(10)(11)(12)(13)(14). We have carried this important observation one step further by proposing that there is a specific number ofreceptors that must be linked together in order to deliver the triggering signal (15). The interaction site between antigen and receptor often has been proposed as occurring on the surface of B lymphocytes (16). Various kinds of antigen-presenting cells also may play a role at this site (17, 18); however, for the sake of simplicity, we have taken the limiting step to be one occurring on the external surfaces of B cells. We have described the preparation of and the in vivo immunological response to a series ofsize-fractionated linear polymers of acrylamide partially substituted with dinitrophenyl (Dnp) hapten (15), which behaved as "T cell-independent" antigens. Analysis of the responses elicited by a series of such polymer preparations led us to the conclusion that the primary immunological response at some basic and limiting level is quantized-i. e., a minimum specific number of antigen receptors (which we estimated to be -12-16) must be connected together as a spatially compact cluster, an "immunon," before an immunogenic signal is delivered to the receptor cell.The present paper gives the results ofusing size-fractionated Dnp-polyacrylamide preparation...

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Separate Signals for the Initiation of Proliferation and Differentiation in the B Cell Response to Antigen

Cited by 54 publications

References 39 publications

Development of a human T-cell hybridoma secreting separate B-cell growth and differentiation factors.

Development of a human T-cell hybridoma secreting separate B-cell growth and differentiation factors.

Induction of an antibody response in cultures of human peripheral blood lymphocytes.

Specific cellular stimulation in the primary immune response: experimental test of a quantized model.

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