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...

The characteristics, importance, and molecular requirements for interactions between mast cells (MCs) and CD8(+) T cells have not been elucidated. Here, we demonstrated that MCs induced antigen-specific CD8(+) T cell activation and proliferation. This process required direct cell contact and MHC class I-dependent antigen cross-presentation by MCs and induced the secretion of interleukin-2, interferon-gamma, and macrophage inflammatory protein-1alpha by CD8(+) T cells. MCs regulated antigen-specific CD8(+) T cell cytotoxicity by increasing granzyme B expression and by promoting CD8(+) T cell degranulation. Because MCs also upregulated their expression of costimulatory molecules (4-1BB) and released osteopontin upon direct T cell contact, MC-T cell interactions probably are bidirectional. In vivo, adoptive transfer of antigen-pulsed MCs induced MHC class I-dependent, antigen-specific CD8(+) T cell proliferation, and MCs regulated CD8(+) T cell-specific priming in experimental autoimmune encephalomyelitis. Thus, MCs are important players in antigen-specific regulation of CD8(+) T cells.

Mast cells (MCs), which are well known for their effector functions in T H 2-skewed allergic and also autoimmune inflammation, have become increasingly acknowledged for their role in protection of health. It is now clear that they are also key modulators of immune responses at interface organs, such as the skin or gut. MCs can prime tissues for adequate inflammatory responses and cooperate with dendritic cells in T-cell activation. They also regulate harmful immune responses in trauma and help to successfully orchestrate pregnancy. This review focuses on the beneficial effects of MCs on tissue homeostasis and elimination of toxins or venoms. MCs can enhance pathogen clearance in many bacterial, viral, and parasitic infections, such as through Toll-like receptor 2-triggered degranulation, secretion of antimicrobial cathelicidins, neutrophil recruitment, or provision of extracellular DNA traps. The role of MCs in tumors is more ambiguous; however, encouraging new findings show they can change the tumor microenvironment toward antitumor immunity when adequately triggered. Uterine tissue remodeling by a-chymase (mast cell protease [MCP] 5) is crucial for successful embryo implantation. MCP-4 and the tryptase MCP-6 emerge to be protective in central nervous system trauma by reducing inflammatory damage and excessive scar formation, thereby protecting axon growth. Last but not least, proteases, such as carboxypeptidase A, released by FcεRIactivated MCs detoxify an increasing number of venoms and endogenous toxins. A better understanding of the plasticity of MCs will help improve these advantageous effects and hint at ways to cut down detrimental MC actions.

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.