Interleukin-4 (IL-4) is a pleiotropic lymphokine which plays an important role in the immune system. IL-4 activates two distinct signalling pathways through tyrosine phosphorylation of Stat6, a signal transducer and activator of transcription, and of a 170K protein called 4PS. To investigate the functional role of Stat6 in IL-4 signalling, we generated mice deficient in Stat6 by gene targeting. We report here that in the mutant mice, expression of CD23 and major histocompatibility complex (MHC) class II in resting B cells was not enhanced in response to IL-4. IL-4 induced B-cell proliferation costimulated by anti-IgM antibody was abolished. The T-cell proliferative response was also notably reduced. Furthermore, production of Th2 cytokines from T cells as well as IgE and IgG1 responses after nematode infection were profoundly reduced. These findings agreed with those obtained in IL-4 deficient mice or using antibodies to IL-4 and the IL-4 receptor. We conclude that Stat6 plays a central role in exerting IL-4 mediated biological responses.

When stimulated with antigen, B cells are influenced by T cells to proliferate and differentiate into antibody-forming cells. Since it was reported that soluble factors could replace certain functions of helper T cells in the antibody response, several different kinds of lymphokines and monokines have been reported in B-cell growth and differentiation. Among these, human B-cell differentiation factor (BCDF or BSF-2) has been shown to induce the final maturation of B cells into immunoglobulin-secreting cells. BSF-2 was purified to homogeneity and its partial NH2-terminal amino-acid sequence was determined. These studies indicated that BSF-2 is functionally and structurally unlike other known proteins. Here, we report the molecular cloning, structural analysis and functional expression of the cDNA encoding human BSF-2. The primary sequence of BSF-2 deduced from the cDNA reveals that BSF-2 is a novel interleukin consisting of 184 amino acids.

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Human B-cell differentiation factor (BCDF) was purified to homogeneity by sequential fitration and chromatography of culture supernatants from TCL-Nal cells on an AcA34 gel column and then on a Mono P column with fast protein liquid chromatography and reversed-phase HPLC. A 5300-fold enrichment in specific activity of BCDF with about 25% recovery was attained.

IL-18, produced as a biologically inactive precursor, is processed by caspase-1 in LPS-activated macrophages. Here, we investigated caspase-1-independent processing of IL-18 in Fas ligand (FasL)-stimulated macrophages and its involvement in liver injury. Administration of Propionibacterium acnes (P. acnes) upregulated functional Fas expression on macrophages in an IFNgamma-dependent manner, and these macrophages became competent to secrete mature IL-18 upon stimulation with FasL. This was also the case for caspase-1-deficient mice. Administration of recombinant soluble FasL (rFasL) after P. acnes priming induced comparable elevation of serum IL-18 in parallel with elevated serum liver enzyme levels. However, liver injury was not induced in IL-18-deficient mice after rFasL administration. These results indicate a caspase-1-independent pathway of IL-18 secretion from FasL-stimulated macrophages and its critical involvement in FasL-induced liver injury.

The class IV semaphorin Sema4A provides a costimulatory signal to T cells. To investigate the possible developmental and regulatory roles of Sema4A in vivo, we generated Sema4A-deficient mice. Although Sema4A-deficient mice develop normally, DCs and T cells from knockout mice display poor allostimulatory activities and T helper cell (Th) differentiation, respectively. Interestingly, in addition to its expression on DCs, Sema4A is upregulated on Th1-differentiating cells, and it is necessary for in vitro Th1 differentiation and T-bet expression. Consequently, in vivo antigen-specific T cell priming and antibody responses against T cell-dependent antigens are impaired in the mutant mice. Additionally, Sema4A-deficient mice exhibit defective Th1 responses. Furthermore, reconstitution studies with antigen-pulsed DCs reveal that DC-derived Sema4A is important for T cell priming, while T cell-derived Sema4A is involved in developing Th1 responses. Collectively, these results indicate a nonredundant role of Sema4A not only in T cell priming, but also in the regulation of Th1/Th2 responses.

T1/ST2, an orphan receptor with homology with the interleukin (IL)-1 receptor family, is expressed constitutively and stably on the surface of T helper type 2 (Th2) cells, but not on Th1 cells. T1/ST2 is also expressed on mast cells, which are critical for Th2-mediated effector responses. To evaluate whether T1/ST2 is required for Th2 responses and mast cell function, we have generated T1/ST2-deficient (T1/ST2−/−) mice and examined the roles of T1/ST2. Naive CD4+ T cells isolated from T1/ST2−/− mice developed to Th2 cells in response to IL-4 in vitro. T1/ST2−/− mice showed normal Th2 responses after infection with the helminthic parasite Nippostrongylus brasiliensis as well as in the mouse model of allergen-induced airway inflammation. In addition, differentiation and function of bone marrow–derived cultured mast cells were unaffected. These findings demonstrate that T1/ST2 does not play an essential role in development and function of Th2 cells and mast cells.