Apoptosis of the WEHI 231 immature B cell lymphoma line following membrane interaction with an antibody against the surface IgM chains (anti‐IgM) is preceded by dramatic changes in Nuclear Factor‐kappaB (NF‐kappaB)/ Rel binding activities. An early transient increase in NF‐kappaB/Rel binding is followed by a significant decrease in intensity below basal levels. Here we have explored the role of these changes in Rel‐related factors in B cell apoptosis. Treatment of WEH1 231 cells with N‐tosyl‐L‐phenylalanine chloromethyl ketone (TPCK), a protease inhibitor which prevents degradation of the inhibitor of NF‐kappaB (IkappaB)‐alpha, or with low doses of pyrrolidinedithiocarbamate (PDTC) selectively inhibited NF‐kappaB/Rel factor binding and induced apoptosis. Bcl‐XL expression protected WEHI 231 cells from apoptosis induced by these agents. Microinjection of WEHI 231 cells with either IkappaB‐alpha‐GST protein or a c‐Rel affinity‐purified antibody induced apoptosis. Ectopic c‐Rel expression ablated apoptosis induced by TPCK or anti‐IgM. Treatment of BALENLM 17 and A20 B lymphoma cells or normal murine splenic B lymphocytes with either TPCK or PDTC also resulted in apoptosis. These findings indicate that the drop in NF‐kappaB/Rel binding following anti‐IgM treatment activates apoptosis of WEHI 231 cells; furthermore, they implicate the NF‐kappaB/Rel family in control of apoptosis of normal and transformed B cells.

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We used congenic-resistant mouse strains to answer questions concerning the respective roles of genes coding for major histocompatibility and background genotypes in T (thymus-derived)-B (bone marrow-derived) lymphocyte cooperative responses to hapten-protein conjugates. These studies demonstrate conclusively that the gene or genes present in the H-2 complex control the capacity of antigen-specific T and B cells to effectively interact. These findings led us to postulate that there exists on the B-lymphocyte surface an "acceptor" molecule for the active T-cell product or for the T cell itself.

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In the studies reported here, we have analyzed the production and consumption of T cell growth factor, more recently termed interleukin 2 (IL-2), as well as some cell-mediated immune functions, in murine strains [MRL, BXSB, NZB, and (NZB x NZWF1] manifesting systemic lupus erythematosus (SLE)-like syndromes. Young (4-6 wk) or old (4-8 mo) autoimmune or normal mice were studied and compared with regard to the following T cell functions in vitro after stimulation with concanavalin A (Con A): (a) mitogenic response; (b) IL-2 levels in culture supernates; and (c) the ability to respond to and adsorb IL-2. In addition, proliferative activity in the allogeneic mixed leukocyte culture and frequency of alloreactive cytotoxic T lymphocyte precursors (CTLp) were analyzed in some of these strains. Reduced Con A-induced mitogenic responses and IL-2 production appeared at 3-6 wk of age in the early, severe SLE developing strains MRL-Mp-lpr/lpr (MRL/l) and male BXSB and progressed thereafter. Similar defects appeared at a later stage in MRL/Mp-+/+ and (NZB x NZW)F1 hybrid mice, which develop late disease. Detailed analysis of cells from the enlarged lymph nodes and spleens of older MRL/l mice demonstrated that such cells: (a) responded poorly to Con A or allogeneic stimulator cells, even in the presence of exogenous IL-2; (b) did not suppress IL-2 production by normal spleen cells; (c) were relatively incapable of adsorbing or inactivating IL-2; and (d) had a markedly reduced anti-H-2b CTLp frequency in the mesenteric lymph nodes but a normal one in spleen. These results indicate that the proliferating Thy-1.2+, Lyt-1+ T cells in MRL/l mice are defective in their responses to mitogenic stimuli, in IL-2 production, and in expression of acceptor sites for IL-2. The relevance of these defects to the MRL/l disease as well as to the role of IL-2 in autoimmunity in general remains to be determined.

The introduction of defned haptenic determinants into immunogenic carriers by Landsteiner (1) has provided a poweriul tool for the analysis of specific interactions between antigens and specific ceils in the immune response. Considerable evidence has been obtained demonstrating that cellular immune reactions to hapten-protein conjugates (delayed sensitivity [2-@ stimulation of DNA synthesis by antigen [7,8], and hapten-specific secondary responses [9-111) display a significant although variable degree of carrier specificity. Such carrier specificity of hapten-specific cellular reactions was initially interpreted to reflect the partial specificity of the antigen-binding receptors of specific cells for the carrier molecule (12-16), paralleling the demonstrated carrier specificity of anfi-hapten humoral antibodies (16)(17)(18).This interpretation of carrier function, however, is not able to explain several essential characteristics of hapten-specific immune responses:(a) The magnitude of the carrier specificity of cellular immune reactions cannot be easily explained by the relatively modest contribution, in energetic terms, of the carrier molecule to the specificity of most anti-hapten humoral antibodies (16-18):(b) Hapten conjugates of immunogenic molecules are required to elicit strong antihapten antibody responses; nonimmunogenic substances serve only poorly, or not at all, as carriers for haptens (19)(20)(21).(e) The induction of immunological unresponsiveness to the carrier molecule results in the partial or total suppression of the responses to haptens on the tolerated proteins (22)(23)(24)(25)(26)(27).If the specificity of serum antibody accurately expresses the specificity of the antigenbinding receptors present on the precursors of antibody forming cells, then these findings suggest the operation o[ an additional recognition mechanism for the carrier molecule. This interpretation would be strengthened if cooperation between carrier-specific and hapten-specific cells were found to be essential for the development of anti-hapten immune responses. According to this view, cells capable o[ reacting with carrier molecules should interact with the antigen be[ore anti-hapten antibody producing cells could be stimulated by hapten-protein conjugates.Mitchison (28) and Rajewsky et al. (29), have recently demonstrated such cooperation between carrier-specific cells and hapten-specific cells in anti-hapten secondary 261