B cell growth-promoting activities have recently been described by a number of investigators in both mouse and human models. These activities have been identified in mitogen-induced culture supernatants of normal cells (1, 2), cell lines (3-5), and hybridomas (6-13). These B cell growth factor (BCGF) ~ activities have been detected and measured in a number of different assays. These include the measurement of the proliferation of normal B cells after costimulation with anti-Ig (6, 7, 12, 13) or mitogens (2,9,10,12,14), or direct stimulation of B cells from B cell lymphomas (1-3, 11). Since the assay systems and the sources of the lymphokine activities have varied between individual investigators, it has not been possible to conclude whether one or more different factors were responsible for B cell proliferation. Some of us recently described (3) a growth factor from the Dennert line C.C3.11.75, termed (DL)BCGF, 2 which maintained the growth of the in vivo BCL~ tumor line and appeared to bind to receptors on the tumor cells (3). In our early attempts to characterize this material, it was clear that it was unusually * Supported by grants AI-08795 and CA-09174 from the National Institutes of Health (NIH), grant IM-1P from the American Cancer Society, and grant 81-173 from the American Heart Association.Laboratory 2 Factor preparation nomenclature: Since the possible relationships of different factors are unknown, we have designated factor preparations other than IL-1 and IL-2 by their activity (e.g., a preparation that has activity in a B cell growth assay is designated BCGF), preceded in parentheses by an indication of the cell line source of the relevant hybridoma (e.g., BCGF from the DL line is designated (DL)BCGF). 822J. ExP. MED.

The initial studies on T cell replacing factors were carried at a time when the complexity ofthe cell interactions in the B cell response to antigen had yet to be fully appreciated. The requirement for helper T cells was demonstrated by the studies of Claman and his colleagues, and by Mitchell, Miller, and others. The work of Mitchison, Rajewsky and other demonstrated that the T cells were also antigen-specific and that there was a need for "linked recognition". That is to say that the antigen determinants recognized by the T cell had to be physically associated with the antigen determinants recognized by the B cell. This was at first taken as evidence for a need for direct cell-cell interaction between T cell and B cell, but it was soon realized that the same experiments could be accommodated by a model in which T cell help was mediated by small amounts of a locally effective T cell mediator.That the response of T cell-depleted spleens could in fact be restored by T cellderived mediators was first demonstrated in our laboratory (Dutton et al. 1971) and by Schimpl & Wecker (1972). Our experiment made use ofthe observation that large numbers of T cells were activated when MHC-disparate lymphocytes were mixed and showed that mixed lymphocyte reaction (MLR) culture supernatants contained a T cell replacing factor. It was quickly shown that other culture supernatants of concanavalin A (Con A) or antigen-activated T cells contained a similar activity (Andersson et al. 1972).The picture became more complicated when it was shown that such culture supernatants would not replace T cells in all B cell responses. Thus it was shown that histocompatible antigen-specific T cells were required in the response of

The in vitro effects of recombinant interleukin (IL) 5 on proliferation and maturation of mouse Ly-1 B cells were studied. Most freshly isolated peritoneal Ly-1 B cells expressed high levels of IL5 receptor (R). Limiting dilution analyses showed that mitogens could reveal IL5 responsiveness in more than half of low density peritoneal Ly-1 B cells. IL 5 was able not only to increase the proportion of these Ly-1 B cells induced to proliferate, but it also shifted the clone size distribution of proliferating cells towards larger clone sizes. Splenic Ly-1 B cells also proliferated in response to mitogens plus IL5. Spontaneous and polyclonal activator-induced plaque-forming cell responses of Ly-1 B cells were increased by IL5. Furthermore, IL5 increased the frequency of peritoneal Ly-1 B cells induced to secrete certain autoantibodies. IL5 was certainly the agent responsible since its effects on both proliferation and differentiation were inhibited by either anti-IL5R monoclonal antibodies or by anti-IL5 monoclonal antibodies. Hence, Ly-1 B cells, IL5 and the IL5R appear to constitute a system of cellular proliferation, differentiation and some autoantibody production. Strategies specifically targeting the interleukin and receptor elements of this system might afford external control of these cellular responses.

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A cloned cell line of thymic origin has been characterized as epithelial in nature. A description of the procedures for derivation and cloning of the cell line includes use of epidermal growth factor. The thymic epithelial (TEPI) cell line is Ia antigen positive, forms desmosomes, and produces an extracellular fibronectin matrix. The supernatant from confluent monolayers of TEPI was tested for its ability to promote thymocyte functional activity. TEPI supernatant (TEPI SN) was demonstrated to greatly enhance the response of peanut agglutinin-positive thymocytes to alloantigen, as measured by cell-mediated lympholysis. Furthermore, preincubation of peanut agglutininpositive thymocytes with TEPI SN prior to allostimulation resulted in marked enhancement, thus distinguishing it from interleukin 2. Finally, TEPI SN was demonstrated to induce interleukin 2 production by peanut agglutinin-positive thymocytes in the presence of concanavalin A. This activity was demonstrated not to be due to-interleukin 1, which is absent in TEPI SN. Preliminary biochemical analysis indicates that the biological activity is associated with a Mr 50,000 entity. The data suggest that TEPI produces asoluble factor capable of inducing function of an immature thymocyte subpopulation into an IL 2 producer.