The chemokines are a large family of small, structurally related cytokines. The physiological importance of most members of this family has yet to be elucidated, although some are inducible inflammatory mediators that determine leukocyte chemotaxis. Pre-B-cell growth-stimulating factor/stromal cell-derived factor-1 (PBSF/SDF-1) is a member of the CXC group of chemokines PBSF/SDF-1 stimulates proliferation of B-cell progenitors in vitro and is constitutively expressed in bone-marrow-derived stromal cells. Here we investigate the physiological roles of PBSF/SDF-1 by generating mutant mice with a targeted disruption of the gene encoding PBSF/SDF-1. We found that mice lacking PBSF/SDF-1 died perinatally and that although the numbers of B-cell progenitors in mutant embryos were severely reduced in fetal liver and bone marrow, myeloid progenitors were reduced only in the bone marrow but not in the fetal liver, indicating that PBSF/SDF-1 is responsible for B-cell lymphopoiesis and bone-marrow myelopoiesis. In addition, the mutants had a cardiac ventricular septal defect. Hence, we have shown that the chemokine PBSF/SDF-1 has several essential functions in development.

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Rheumatoid arthritis is a common and debilitating autoimmune disease whose cause and mechanism remain a mystery. We recently described a T cell receptor transgenic mouse model that spontaneously develops a disease with most of the clinical, histological, and immunological features of rheumatoid arthritis in humans. Disease development in K/BxN mice is initiated by systemic T cell self-reactivity; it requires T cells, as expected, but B cells are also needed, more surprisingly. Here, we have identified the role of B cells as the secretion of arthritogenic immunoglobulins. We suggest that a similar scenario may unfold in some other arthritis models and in human patients, beginning with pervasive T cell autoreactivity and ending in immunoglobulin-provoked joint destruction.

Generation and proliferation of early B-cell progenitors have been known to require stromal cell-derived molecules. A stromal cell line, PA6, was found to produce a soluble mediator, which was distinct from interleukin 7 (IL-7) and stem cell factor and supported the proliferation of a stromal cell-dependent pre-B-cell done, DW34. A cDNA clone encoding this DW34 growth-stimulating factor was isolated by expression cloning. The nucleotide sequence contained a single substantial open reading frame of 267 nucleotides encoding an 89-amino acid polypeptide. The amino acid sequence of this cytokine, designated pre-B-cell growth-stimulating factor (PBSF), revealed that it is a member of intercrine a subfamily. Recombinant PBSF stimulated the proliferation of DW34 cells for itself and, furthermore, synergistically augmented the growth of DW34 as well as bone marrow B-cell progenitors in the presence of IL-7.It is well known that stromal cells play an important role in bone marrow B lyimphopoiesis. Whitlock and Witte (1) have developed an in vitro long-term B lymphopoiesis system that maintains B-cell progenitors on bone marrow-derived heterogenous stromal cells. In addition, several stromal cell lines that can support long-term B lymphopoiesis have been established (2-7). These cell lines have been used to study the environmental components required for B lymphopoiesis. For example, interleukin 7 (IL-7) (8) was cloned from a stromal cell line and shown to play a key role in B lymphopoiesis (9). However, it appears that IL-7 alone is not sufficient to support B lymphopoiesis in the bone marrow (10-12). Hayashi et al. (10) suggested that IL-7 and unidentified molecules produced by stromal cell line PA6 (13) were required for B lymphopoiesis. They showed that B-cell development proceeded through three sequential stages in terms of the growth signal requirement. At the first stage, the cells required PA6 alone for proliferation and differentiated into the second stage, where cells required both PA6 and IL-7 for growth. Then some cells at the second stage acquired the ability to proliferate in response to IL-7 alone. Rolink et al. (11) showed that PA6 potentiated the proliferative effect of IL-7 on early pre-B-cell clones that developed to mature B cells. However, these PA6-derived molecules involved in B lymphopoiesis have not yet been identified. One candidate stromal cell-derived molecule is stem cell factor (SCF) (14)(15)(16), since it synergizes with IL-7 in stimulating the proliferation of B-cell progenitors (17). However, recent studies showed that B lymphopoiesis was not significantly affected by injection of the antagonistic anti-SCF receptor monoclonal antibody (mAb) ACK2, although myeloid and erythroid hemopoiesis was severely inhibited (18). Therefore, it appears that there are unidentified molecules that compensate the function of neutralized SCF. In this paper, we report a cDNA clone encoding a pre-B-cell growth-stimulating factor (PBSF) that promotes the growth of B-cell progenitors; we show that PBSF i...

Semaphorins are axon guidance factors that assist growing axons in finding appropriate targets and forming synapses. Emerging evidence suggests that semaphorins are involved not only in embryonic development but also in immune responses. Semaphorin 7A (Sema7A; also known as CD108), which is a glycosylphosphatidylinositol-anchored semaphorin, promotes axon outgrowth through beta1-integrin receptors and contributes to the formation of the lateral olfactory tract. Although Sema7A has been shown to stimulate human monocytes, its function as a negative regulator of T-cell responses has also been reported. Thus, the precise function of Sema7A in the immune system remains unclear. Here we show that Sema7A, which is expressed on activated T cells, stimulates cytokine production in monocytes and macrophages through alpha1beta1 integrin (also known as very late antigen-1) as a component of the immunological synapse, and is critical for the effector phase of the inflammatory immune response. Sema7A-deficient (Sema7a-/-) mice are defective in cell-mediated immune responses such as contact hypersensitivity and experimental autoimmune encephalomyelitis. Although antigen-specific and cytokine-producing effector T cells can develop and migrate into antigen-challenged sites in Sema7a-/- mice, Sema7a-/- T cells fail to induce contact hypersensitivity even when directly injected into the antigen-challenged sites. Thus, the interaction between Sema7A and alpha1beta1 integrin is crucial at the site of inflammation. These findings not only identify a function of Sema7A as an effector molecule in T-cell-mediated inflammation, but also reveal a mechanism of integrin-mediated immune regulation.