Search

The extracellular matrix in asthmatic lungs contains abundant low-molecular-weight hyaluronan, and this is known to promote antigen presentation and allergic responses. Conversely, high-molecular-weight hyaluronan (HMW-HA), typical of uninflamed tissues, is known to suppress inflammation. We investigated whether HMW-HA can be adapted to promote tolerance to airway allergens. HMW-HA was thiolated to prevent its catabolism and was tethered to allergens via thiol linkages. This platform, which we call "XHA," delivers antigenic payloads in the context of antiinflammatory costimulation. Allergen/XHA was administered intranasally to mice that had been sensitized previously to these allergens. XHA prevents allergic airway inflammation in mice sensitized previously to either ovalbumin or cockroach proteins. Allergen/XHA treatment reduced inflammatory cell counts, airway hyperresponsiveness, allergen-specific IgE, and T helper type 2 cell cytokine production in comparison with allergen alone. These effects were allergen specific and IL-10 dependent. They were durable for weeks after the last challenge, providing a substantial advantage over the current desensitization protocols. Mechanistically, XHA promoted CD44-dependent inhibition of nuclear factor-κB signaling, diminished dendritic cell maturation, and reduced the induction of allergen-specific CD4 T-helper responses. XHA and other potential strategies that target CD44 are promising alternatives for the treatment of asthma and allergic sinusitis.

TRAIL (TNF-related apoptosis-inducing ligand) is a member of the TNF family that induces apoptosis in a variety of cancer cells. In this study, we demonstrate that human CD11c(+) blood dendritic cells (DCs) express TRAIL after stimulation with either interferon (IFN)-gamma or -alpha and acquire the ability to kill TRAIL-sensitive tumor cell targets but not TRAIL-resistant tumor cells or normal cell types. The DC-mediated apoptosis was TRAIL specific, as soluble TRAIL receptor blocked target cell death. Moreover, IFN-stimulated interleukin (IL)-3 receptor (R)alpha(+) blood precursor (pre-)DCs displayed minimal cytotoxicity toward the same target cells, demonstrating a clear functional difference between the CD11c(+) DC and IL-3Ralpha(+) pre-DC subsets. These results indicate that TRAIL may serve as an innate effector molecule on CD11c(+) DCs for the elimination of spontaneously arising tumor cells and suggest a means by which TRAIL-expressing DCs may regulate or eliminate T cells responding to antigen presented by the DCs.

Identification of a counterstructure for the human cytomegalovirus-encoded major histocompatibility complex class I-related gene product, UL18, has led to the discovery of a novel family of immunoreceptors, termed leukocyte immunoglobulin-like receptors (LIRs). The LIRs are differentially expressed in cells of the dendritic cell, monocytic and lymphocytic lineages, and appear to mediate diverse roles in immune regulation. This review summarizes the expression, distribution, and signaling capacities of the LIRs and discusses possible roles of the LIRs in both inhibition and activation of the cellular responses. J. Leukoc. Biol. 66: 231–236; 1999.

The MHC class I binding proteins leukocyte immunoglobulin-like receptor (LIR)-1 and −2 recognize a similar broad spectrum of HLA-A, -B and -C alleles but are differentially expressed in lymphocytes, monocytes, and dendritic cells. In monocytes, phosphorylation of LIR-1 and LIR-2 results in the binding of the tyrosine phosphatase SHP-1. Coligation of either LIR with Fcγ receptor I (CD64) inhibits tyrosine phosphorylation of the associated Fc receptor γ chain and Syk molecules, as well as intracellular calcium mobilization. These findings suggest that LIR-1 and LIR-2 function as unique MHC class I receptors involved in the inhibition or down-modulation of monocyte activation signals, particularly those mediated through the receptors for IgG, IgE and IgA.

The intestine is under perpetual challenge from both pathogens and essential nutrients, yet the mucosal immune system is able to discriminate effectively between harmful and innocuous Ags. It is likely that this selective immunoregulation is dependent on the nature of the APC at sites where gut Ags are processed and presented. Dendritic cells (DC) are considered the most potent of APC and are renowned for their immunostimulatory role in the initiation of immune responses. To investigate the role of DC in regulating the homeostatic balance between mucosal immunity and tolerance, we treated mice with Flt3 ligand (Flt3L), a growth factor that expands DC in vivo, and assessed subsequent systemic immune responsiveness using mouse models of oral tolerance. Surprisingly, mice treated with Flt3L to expand DC exhibited more profound systemic tolerance after they were fed soluble Ag. Most notably, tolerance could be induced in Flt3L-treated mice using very low doses of Ag that were ineffective in control animals. These findings contrast with the generally accepted view of DC as immunostimulatory APC and furthermore suggest a pivotal role for DC during the induction of tolerance following mucosal administration of Ag.

The lymphotoxin beta receptor (LTbetaR), and its ligand, LTalpha1beta2, have been proposed to play a key role in the development and organization of lymphoid tissues. The LTbetaR is expressed on a variety of human primary and transformed cells, but strikingly absent on T or B lymphocytes and primary monocytes or peripheral dendritic cells, although LTbetaR is detected on some myeloid leukemic lines. In the developing thymus LTbetaR is prominent along the trabeculae and into the medulla upto corticomedullary junction. In the spleen, LTbetaR is prominently expressed by cells in the red pulp and along the borders of red and white pulp which colocalizes with reticular stromal cells. The LTbetaR is expressed on a human follicular dendritic cell line, FDC-1, and signals expression of CD54 when ligated with the LTalpha1beta2 complex. These results support the concept that directional interactions between LTalpha1beta2 bearing lymphocytes and LTbetaR bearing stromal cells are involved in the organization of lymphoid tissue.

The primary function of polymorphonuclear neutrophils (PMN) in the immune response appears to be acute phagocytic clearance of foreign pathogens and release of inflammatory mediators. Consistent with their assumed lack of major histocompatibility complex (MHC) class II expression, PMN have not been considered to play a role in antigen presentation and T-cell activation. However, recent reports have shown that human PMN can express MHC class II molecules both in vitro and in vivo after stimulation with either granulocyte-macrophage colony-stimulating factor (GM-CSF ) or interferon-γ (IFN-γ). Thus, under appropriate conditions, PMN could play a significant role in immune regulation, including T-cell activation. In this report, we demonstrate that human class II–expressing PMN can serve as accessory cells in superantigen (SAg)-mediated T-cell activation. This accessory activity for SAg presentation was present only after induction of MHC class II expression, and was especially pronounced following culture of PMN with GM-CSF plus IFN-γ, which acted synergistically to induce MHC class II molecules on PMN. Moreover, the level of MHC class II expression and the magnitude of SAg-induced T-cell responses were found to be highly correlated and distinctly donor dependent, with PMN from some donors repeatedly showing fivefold higher responses than PMN from other donors. On the other hand, culture of PMN with GM-CSF plus IFN-γ under conditions that resulted in optimal MHC class II expression did not enable them to function as antigen-presenting cells for either intact tetanus toxoid (TT) or for a TT peptide. These results delineate a new pathway for T-cell activation by SAg that may play an important role in the severity of SAg-induced inflammatory responses. They also identify a donor-specific polymorphism for induction of PMN MHC class II expression which may be of significance for therapies involving GM-CSF and IFN-γ.

Fc receptors specific for IgG (FcγR) potentiate the immune response by facilitating the interaction between myeloid cells and antibody-coated targets (1-3). Monocyte and neutrophil FcyR engagement can lead to the induction of lytic-type mechanisms associated with innate responses. FcyR triggering can also play a key role in adaptive immune responses. For example, FcyR-directed capture and uptake of antigens (Ag) by dendritic cells (DC) results in processing and presentation to naive Ag-specific T cells, leading to their expansion and maturation into effector T-cell populations. This chapter describes methodology currently in use to explore and manipulate antigen-antibody (Ag-Ab) uptake by FcyR expressed on DC.

The use of glycoproteins encoded by human cytomegalovirus as probes to isolate their cellular counterstructures has resulted in the discovery of novel immunoreceptors. The HCMV-encoded MHC class I homolog, UL18, binds to LIR-1/ILT2, an inhibitory signaling receptor for cellular MHC class I antigens with a broad distribution on leukocytes, including some NK cells. Although UL18 has been proposed to act as an inhibitor of NK cytotoxicity, this remains controversial. Another HCMV-encoded glycoprotein, UL16, binds to members of a novel non-classical MHC class I-related family, the ULBPs, as well as to MICB, a known non-classical MHC class I antigen. The MICs and ULBPs are ligands for the activating receptor, NKG2D/DAP10, expressed by NK and other immune effector cells. Ligation of NKG2D/DAP10 by ULBPs or MICs on a target cell can overcome an inhibitory signal mediated by NK recognition of MHC class I antigens and allow NK cytotoxicity. ULI6 masking of ULBP or MIC recognition may represent a mechanism of immune evasion by CMV.

The human cytomegalovirus UL18 protein, an MHC class I homologue, has been shown to bind to leucocyte immunoglobulin-like receptor (LIR)-1, a member of a family of nine closely related immunoglobulin superfamily receptors expressed on leucocytes. The LIRs are related to the natural killer (NK)-cell immunoglobulin-like receptors and to several other immunoreceptors. Three groups of LIR molecules have been defined: those containing cytoplasmic domain inhibitory signalling motifs, those with short cytoplasmic domains and a charged residue within the transmembrane domain, and a secreted molecule. LIR-1 and LIR-2 bind to a broad spectrum of cellular MHC class I antigens, including HLA-A, -B and -C alleles. LIR-2 is expressed by all monocytes and dendritic cells, whereas LIR-1 is additionally expressed by B cells and subsets of T and NK cells. Upon tyrosine phosphorylation, LIR-1 and LIR-2 associate with the tyrosine phosphatase, SHP-1, and have been shown to inhibit Fc gamma RI signalling when co-crosslinked in monocytes. Evidence for and against a role of UL18 as an inhibitor of NK-cell function is discussed, as are possible functional outcomes of UL18-LIR-1 interactions in monocytic cells.

TRAIL (tumor necrosis factor [TNF]-related apoptosis-inducing ligand) is a molecule that displays potent antitumor activity against selected targets. The results presented here demonstrate that human monocytes rapidly express TRAIL, but not Fas ligand or TNF, after activation with interferon (IFN)-γ or -α and acquire the ability to kill tumor cells. Monocyte-mediated tumor cell apoptosis was TRAIL specific, as it could be inhibited with soluble TRAIL receptor. Moreover, IFN stimulation caused a concomitant loss of TRAIL receptor 2 expression, which coincides with monocyte acquisition of resistance to TRAIL-mediated apoptosis. These results define a novel mechanism of monocyte-induced cell cytotoxicity that requires TRAIL, and suggest that TRAIL is a key effector molecule in antitumor activity in vivo.