TLR3-induced activation of mast cells modulates CD8+ T-cell recruitment

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...

The therapeutic effects of sodium cromoglycate against influenza A virus H5N1 in mice

“…In contrast, the expression of TNF‐α and IL‐6 was decreased significantly on days 3 and 5 pi in SCG‐treated mice, which suggests that SCG could improve the mortality of virus‐infected mice by preventing the overproduction of proinflammatory cytokines. Many studies have found that mast cells could be involved in virus infection using TLR3, RIG‐I, and MDA5 to sense viral RNA 43, 44, 45. In our study, the expression of TLR3 and TRIF in the lungs of SCG‐treated mice decreased, which suggested that SCG might have some roles in the TLR3 pathway in mast cells during H5N1 infection.…”

Mast cells as rapid innate sensors of cytomegalovirus by TLR3/TRIF signaling-dependent and -independent mechanisms

“…What raised our concern was the previous finding that TLR3/ TRIF signaling in MCs can activate MCs to express costimulatory cell surface molecules and release cytokines and chemokines, but not stimulate degranulation. 15 This contradicts our first interpretation of the data, namely that they would provide evidence for mCMV inducing MC degranulation by directly stimulating the TLR3/TRIF signaling pathway in MCs.…”

“…18 CMV sensitizes MCs for degranulation by inducing TLR3/ TRIF signaling Intraperitoneal application of poly(I : C), a synthetic ligand of PRR TLR3, has been reported to directly upregulate costimulatory molecules and the expression of cytokines and chemokines in MCs, resulting in chemotactic recruitment of CD8 T cells into the peritoneal cavity. 15 In a non-MC-related context, pathogen sensing through TLR3 has been reported for mCMV. 40 We therefore pursued the idea to link that information by testing if the CMV-triggered sensitization of MCs might possibly also be executed through the PRR TLR3 and adapter TRIF signaling pathway ( Figure 1c).…”

“…Specifically, activated MCs release chemokines, such as CCL5, to selectively recruit NK cells, NKT cells and T cells to non-lymphoid sites of immune surveillance. [15][16][17][18] A large body of evidence indicates that release of vasoactive factors, including histamine, heparin, and TNF, by activated MCs can rapidly activate endothelial cells, 1 and this facilitate the extravasation of leukocytes, including T cells, to extravascular sites of infection, although increased vascular permeability can also contribute to MC-mediated immunopathology. 19 As a further link to adaptive immunity, infected MCs can directly serve as antigen-presenting cells by presenting peptides on MHC I and MHC II molecules, and uninfected MCs have been shown to be able to cross-present antigens.…”

Adenovirus-mediated gene transfer of pathogen-associated molecular patterns for cancer immunotherapy

“…26 A major effect of NDV infection is the induction of IFN-a/b secretion, which can be mediated either through TLRs or by RIG-I-dependent signaling. 28,29 NDV-infected autologous tumor cells as vaccines have lead to improvement of patient survival for different cancer types. 30 It is still unclear whether NDV HN has a direct effect on immunostimulatory DCs.…”