No abstract

IntroductionThe magnitude and quality of innate immune response is essential for appropriate adaptive response. The activation of naive CD8 ϩ T cells, the main effector cells in the course of viral infections, their clonal expansion, development of effector cells, and maintenance and expansion of memory CD8 ϩ T cells after antigen reappearance are precisely regulated and dependent on an adequate context of costimulation and cytokine/chemokine environment, provided by cells responding to "first defense line" signals of innate immunity. [1][2][3][4] Mast cells (MCs), pivotal effector cells in immunoglobulin (Ig) E-associated disorders, have recently been recognized as important elements in innate immune defenses. 5 Strategically located at host/environment interfaces like the skin, airways, and gastrointestinal and urogenital tracts, 6,7 MCs are equipped with a large variety of receptors to detect signs of infections including Toll-like receptors (TLRs), CD48, and complement receptors. 8 MCs activated via these receptors secrete a large number of proinflammatory products including granule-associated preformed mediators (histamine, serotonin, proteases, proteoglycans), lipid mediators (leukotrienes B 4 and C 4 and prostaglandins), as well as cytokines, chemokines, and growth factors. 9 In contrast to the well-established crucial role of MCs in induction of host defense responses to bacteria and parasites, the function of MCs in antiviral immune responses remains to be characterized in detail. Recently, a number of reports have shown the functional interplay between MCs and T cells in allergic, infectious, and autoimmune processes, for example, MCs and T cells colocalizing in inflamed tissues, as in the lungs of patients with asthma and in animal models of allergic asthma. 10,11 It has also been reported that tumor necrosis factor ␣ (TNF-␣) released from MCs contributes substantially to T-cell recruitment to the draining lymph nodes (LNs) in an experimental infection model with Escherichia coli. 12 Furthermore, activated MCs induce the chemotaxis of CD8 ϩ T cells through the production of leukotrienes in vitro. 13 Further, the recruitment of early effector T cells into the airways in an asthma model is mediated by leukotriene B 4 (LTB 4 ) 14 released by MCs activated by IgE cross-linking. 15 However, the mechanisms and relevance of MC-T-cell interactions, as well as the signals required for MC activation and effector functions in settings of viral infections remain largely unknown.TLRs play an important role in innate immunity recognizing specific, nonself, conserved components shared by different pathogens. Different TLRs are involved in the specific recognition of various microbes. 16,17 Human and mouse MCs have been shown to be activated by bacterial peptidoglycan and lipopolysaccharide (LPS) via TLR2 and TLR4, respectively, producing a number of cytokines such as interleukin 5 (IL-5), IL-6, IL-10, IL-13, and TNF-␣. [18][19][20][21] On binding of viral dsRNA or its synthetic counterpart polyinosinic-polycytidyl...

Keratinocytes (KC) are important source of and targets for several cytokines. Although KC express IL-15 mRNA, the functional effects of IL-15 on these epithelial cells remain to be dissected. Investigating primary human foreskin KC and HaCaT cells, we show here by semiquantitative RT-PCR and flow cytometric analysis that both translate IL-15 and IL-15R mRNA and express IL-15 and IL-15Rα protein on the cell surface, suggesting that human KC can employ IL-15 for juxtacrine signaling. While IL-15 exerted no significant effect on KC proliferation and IL-6 or IL-8 secretion, IL-15 inhibited both anti-Fas and methylcellulose-induced KC apoptosis in vitro. This is in line with the recognized potent anti-apoptotic effects of IL-15. IL-2, whose receptor shares two components with the IL-15R, failed to inhibit KC apoptosis. Together with the role of IL-15 in sustaining chronic immune reactions, this invited the question of whether a reduction of KC apoptosis by IL-15 may be involved in the pathogenesis of psoriasis, a chronic hyperproliferative inflammatory skin disease characterized by abnormally low KC apoptosis in the epidermis. Remarkably, compared with nonlesional psoriatic skin and skin of healthy volunteers, lesional psoriatic epidermis showed high IL-15 protein expression in the epidermis and enhanced binding activity for IL-15. Therefore, antagonizing the inhibitory effects of IL-15 on KC apoptosis deserves exploration as a novel therapeutic strategy in psoriasis management.

Interleukin-15 (IL-15) is a potent inhibitor of several apoptosis pathways. One prominent path toward apoptosis is the ligand-induced association of TNF receptor 1 (TNFR1) with death domain adaptor proteins. Studying if and how IL-15 blocks TNFR1-mediated apoptosis in a murine fibroblast cell line (L929), we show here that IL-15 blocks TNFR1-induced apoptosis via IL-15Ralpha chain signaling. The intracellular tail of IL-15Ralpha shows sequence homologies to the TRAF2 binding motifs of CD30 and CD40. Most important, binding of IL-15 to IL-15Ralpha successfully competes with the TNFR1 complex for TRAF2 binding, which may impede assembly of key adaptor proteins to the TNFR1 complex, and induces IkappaBalpha phosphorylation. Thus, IL-15Ralpha chain stimulation is a powerful deflector of cell death very early in the apoptosis signaling cascade, while TNF-alpha and IL-15 surface as major opponents in apoptosis control.

Sepsis remains a global clinical problem. By using the mouse cecal ligation and puncture model of sepsis, here we identify an important aspect of mast cell (MC)-dependent, innate immune defenses against Gram-negative bacteria by demonstrating that MC protease activity is regulated by interleukin-15 (IL-15). Mouse MCs express both constitutive and lipopolysaccharide-inducible IL-15 and store it intracellularly. Deletion of Il15 in mice markedly increases chymase activities, leading to greater MC bactericidal responses, increased processing and activation of neutrophil-recruiting chemokines, and significantly higher survival rates of mice after septic peritonitis. By showing that intracellular IL-15 acts as a specific negative transcriptional regulator of a mouse MC chymase (mast cell protease-2), we provide evidence that defined MC protease activity is transcriptionally regulated by an intracellularly retained cytokine. Our results identify an unexpected breach in MC-dependent innate immune defenses against sepsis and suggest that inhibiting intracellular IL-15 in MCs may improve survival from sepsis.