Interleukin-15 (IL-15) is a potent regulator of T-, B-, and natural killer cell proliferation and displays unusually tight controls of secretion. Even though IL-15 mRNA is constitutively expressed in monocytes/macrophages and is upregulated by a variety of stimuli, evidence for IL-15 cytokine secretion is only found exceptionally, eg, conditions of pathological, chronic inflammation. This raises the possibility that monocytes express membrane-bound IL-15 rather than secrete it. The current study explores this hypothesis. We demonstrate here that biologically active IL-15 is indeed detectable in a constitutively expressed, membrane-bound form on normal human monocytes, as well as on monocytic cell lines (MONO-MAC-6, THP-1, and U937), but not on human T or B cells (MT4, M9, C5966, JURKAT, DAUDI, RAJI, and Epstein-Barr virus-immortalized B-cell clones). Furthermore, cell surface-bound IL-15 is upregulated upon interferon-γ stimulation. Interestingly, monocyte/macrophage inhibitory cytokines such as IL-4 and IL-13 fail to downregulate both constitutive and induced cell-surface expression of IL-15. Membrane-bound IL-15 does not elute with acetate buffer or trypsin treatment, suggesting that it is an integral membrane protein and that it is not associated with the IL-15 receptor complex. Finally, membrane-bound IL-15 stimulates T lymphocytes to proliferate in vitro, indicating that it is biologically active. These findings enlist IL-15 in the fairly small family of cytokines for which the presence of a biologically active membrane-bound form has been demonstrated (eg, IL-1, tumor necrosis factor-, and IL-10) and invites the speculation that most of the biological effects of IL-15 under physiological conditions are exerted by the cell surface-bound form.

Dendritic cells (DCs) initiate adaptive immunity and regulate the inflammatory response by producing inflammatory chemokines. This study was aimed to elucidate their role in the pathogenesis of the suppurative granuloma induced by Bartonella henselae infection, which characterizes cat scratch disease (CSD). In vitro DC infection by B. henselae results in internalization of bacteria, phenotypic maturation with increased expression of HLA-DR and CD86, and induction of CD83, CD208, and CCR7. In comparison to LPSactivated DCs, B henselae-infected DCs produce higher amounts of IL-10, whereas the production of IL-12p70 is reduced. Infected DCs also produce high levels of CXCL8 and CXCL13, 2 chemokines active respectively on neutrophils and B lymphocytes. These results provide the molecular basis for the morphogenesis of CSD granuloma, which typically contains high numbers of neutrophils and B cells. Remarkably, CSD granulomas in vivo contain CXCL13-producing DCs. We further demonstrate that the B cells in CSD granulomas are represented by monocytoid B cells and, worth noting, they express T-bet, a transcription factor able to induce a T-independent immunoglobulin (Ig) class switch in B lymphocytes. These findings suggest that the humoral immune response to B henselae initiates in the extrafollicular areas of infected lymph nodes and is regulated by DCs. IntroductionThe orchestration of the immune response against infections strictly relies on the interaction of pathogens with professional antigen-presenting cells in peripheral tissues. Among them, dendritic cells (DCs) have the unique ability to induce a potent antigen-dependent stimulation and play a central role in the initiation of the primary immune response. 1,2 Indeed, upon exposure to microbial pathogens, DCs migrate to lymph nodes and undergo maturation into potent stimulatory cells. [3][4][5] This process is usually accompanied by Toll-like receptor (TLR) activation that leads to phenotypic and functional changes and by inflammatory cytokine and chemokine production culminating in the recruitment and activation of effector cells. In vivo, DC-derived chemokines are believed to contribute to the recruitment of precursor cells and immature DCs at peripheral inflammation sites and within lymph nodes, where they play a role in T-and B-cell localization. [6][7][8] In terms of immune protection against infectious diseases, nodal granuloma reactions control the systemic spread of pathogens and represent an intriguing model for the effector phase of immune response. The cytokine network involved in the recruitment of DCs in pathologies like the hypersensitivity-type granulomas, typically observed in mycobacterial lymphadenitis, has been extensively investigated. [9][10][11] Hypersensitive-type granulomas are mainly composed by macrophages, macrophage-derived cells such as epithelioid and giant cells, and numerous T lymphocytes, bearing a T-helper 1 (Th1) phenotype. 12 Granulomas resulting from Bartonella henselae infection and associated with cat scratch disease (CS...

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