The class IV semaphorin CD100/Sema4D differentially utilizes two distinct receptors: plexin-B1 in nonlymphoid tissues, such as brain and kidney, and CD72 in lymphoid tissues. We have generated CD100-deficient mice and demonstrated that they have functional defects in their immune system, without apparent abnormalities in other tissues. The number of CD5(+) B-1 cells was considerably decreased in the mutant mice, whereas conventional B cells and T cells appeared to develop normally. In vitro proliferative responses and immunoglobulin production were reduced in CD100-deficient B cells. The humoral immune response against a T cell-dependent antigen and in vivo priming of T cells were also defective in the mutant mice. These results demonstrate nonredundant and essential roles of CD100-CD72 interactions in the immune system.
Semaphorins and their receptors have diverse functions in axon guidance, organogenesis, vascularization and/or angiogenesis, oncogenesis and regulation of immune responses. The primary receptors for semaphorins are members of the plexin family. In particular, plexin-A1, together with ligand-binding neuropilins, transduces repulsive axon guidance signals for soluble class III semaphorins, whereas plexin-A1 has multiple functions in chick cardiogenesis as a receptor for the transmembrane semaphorin, Sema6D, independent of neuropilins. Additionally, plexin-A1 has been implicated in dendritic cell function in the immune system. However, the role of plexin-A1 in vivo, and the mechanisms underlying its pleiotropic functions, remain unclear. Here, we generated plexin-A1-deficient (plexin-A1(-/-)) mice and identified its important roles, not only in immune responses, but also in bone homeostasis. Furthermore, we show that plexin-A1 associates with the triggering receptor expressed on myeloid cells-2 (Trem-2), linking semaphorin-signalling to the immuno-receptor tyrosine-based activation motif (ITAM)-bearing adaptor protein, DAP12. These findings reveal an unexpected role for plexin-A1 and present a novel signalling mechanism for exerting the pleiotropic functions of semaphorins.
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.
We have previously identified two species of the low-affinity human Fc receptor for IgE, FceRIIa and FceRIIb, which differ only in a short stretch of amino acids at the N-terminal cytoplasmic end. (1)(2)(3). FceRII has been known as a B-cell differentiation antigen, CD23 (4-7), and has been proposed to be involved in several B-cell functions such as the growthpromoting effect (8, 9), cell adhesion (10), and IgE-mediated antigen presentation.(11). On the other hand, FceRII has also been reported to be expressed on macrophages, eosinophils, and platelets and to be an effector molecule of IgE-mediated immunity, including immediate-type allergy and cytotoxicity against certain parasites (2). IgE can mediate release of varieties of chemical mediators from eosinophils, monocytes, and platelets (12)(13)(14).We have previously identified two species of human FceRII, FceRIIa and FceRIIb (15, 16). They are generated by utilizing different transcriptional initiation sites and 5' exons of the single genomic gene, and they differed only in a short amino acid stretch in the N-terminal cytoplasmic end. FceRIIa is constitutively, but cell-type-specifically, expressed on B cells. On the other hand, monocytes and eosinophils express only FceRIlb. FceRIIb is expressed on normal peripheral blood B cells and monocytes only after stimulation with interleukin 4, which is known to be the cytokine responsible for the isotype switching of B cells to 5030The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. §1734 solely to indicate this fact.
The transcription factor, Aplysia CCAAT enhancerbinding protein (ApC/EBP), plays a crucial role in long term facilitation, a synaptic mechanism of long term memory in Aplysia. To gain a clue to whether the mammalian C/EBP family of transcription factors are also involved in long term memory, we examined how C/EBP activities in hippocampal neurons can be modulated in response to cAMP and Ca 2؉ , crucial inductive signals for memory formation. As a result, stimulation of either cAMP or Ca 2؉ signals in hippocampal neurons was found to enhance mRNA expressions and DNA binding activities of C/EBP and C/EBP␦. Furthermore, it is indicated that CaM kinases have essential roles for increasing the expression and DNA binding activities of C/EBP in hippocampal neurons activated by membrane depolarization. Overexpression of constitutively active calcium/calmodulin-dependent kinase IV was found to directly stimulate either C/EBP-dependent or C/EBP␦-dependent transcription, reinforcing the evidence that C/EBP family members contribute to Ca 2؉ -dependent transcription. Thus, these results suggest that C/EBP and C/EBP␦ may be involved in the transcription-dependent phase of memory formation by increasing the expression of both the DNA binding and the transcriptional activities under the direction of cAMP and/or Ca 2؉ signaling in hippocampal neurons.
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