Dynamics of dendritic cell–T cell interactions: a role in T cell outcome

Antigen-specific dendritic cells (DC)–T cell encounters occur in lymph nodes (LNs) and are essential for the induction of both priming and tolerance. In both cases, T cells are rapidly activated and proliferate. However, the subsequent outcome of T cell activation depends on the modulation of different DC- and T cell-intrinsic signals. Recent advances in two-photon (2P) microscopy have furthered our understanding regarding the complex choreography of DCs and T cells in intact LNs, and established differences in the dynamics of DC–T cell contacts during priming and tolerance induction. The mechanisms that favour DC–T cell encounters, as well as the contribution of the frequency and the duration of such encounters in dictating the T cell response, are discussed in this review.     

Characteristics of tissue–resident ILCs and their potential as therapeutic targets in mucosal and skin inflammatory diseases

Discovery of innate lymphoid cells (ILCs), which are non–T and non–B lymphocytes that have no antigen-specific receptors, changed the classical concept of the mechanism of allergy, which had been explained mainly as antigen - specific acquired immunity based on IgE and Th2 cells. The discovery led to dramatic improvement in our understanding of the mechanism of non–IgE-mediated allergic inflammation. Numerous studies conducted in the past decade have elucidated the characteristics of each ILC subset in various organs and tissues and their ontogeny. We now know that each ILC subset exhibits heterogeneity. Moreover, the functions and activating/suppressing factors of each ILC subset were found to differ among both organs and types of tissue. Therefore, in this review, we summarize our current knowledge of ILCs by focusing on the organ/tissue - specific features of each subset to understand their roles in various organs. We also discuss ILCs’ involvement in human inflammatory diseases in various organs and potential therapeutic/preventive strategies that target ILCs.     

The regulatory mechanism of β-eudesmol is through the suppression of caspase-1 activation in mast cell–mediated inflammatory response

β-Eudesmol is sesquiterpenoid alcohol which contains the rhizome of Atractylodes lancea. Although it has multiple pharmacological effects, the anti-inflammatory effect of β-eudesmol and its molecular mechanisms are poorly elucidated. In this study, we investigated the regulatory mechanism of β-eudesmol on mast cell–mediated inflammatory response. The results indicated that β-eudesmol inhibited the production and expression of interleukin (IL)-6 on phorbol 12-myristate 13-acetate and calcium ionophore A23187-stimulated human mast cell (HMC). In activated HMC-1 cells, β-eudesmol suppressed activation of p38 mitogen-activated protein kinase (MAPKs) and nuclear factor-κB. In addition, β-eudesmol suppressed the activation of caspase-1 and expression of receptor-interacting protein-2. These results provide new insights into the pharmacological actions of β-eudesmol as a potential molecule for use in therapy in mast cell–mediated inflammatory diseases.     

Regulation of T:B cell interactions by the inducible costimulator molecule: does ICOS "induce" disease?

The Inducible Costimulator molecule (ICOS), a member of the CD28 family of costimulatory molecules, was identified in 1999 as a molecule expressed primarily on activated human T cells. Induced upon activation, ICOS appears to be an ideal target for modifying T-cell-mediated immune responses. ICOS was also found to be highly expressed on germinal center T cells, suggesting that ICOS was involved in T:B cell interactions. While ICOS has subsequently been shown to be important for both Th1 and Th2 cell activation and effector function, a central role for ICOS in the generation and maintenance of humoral immunity is emerging. In this review, we summarize the evidence that the level of ICOS expression regulates T-cell-dependent B cell responses and propose a model for the role of ICOS in diseases characterized by dysregulated humoral immunity.     

Epstein–Barr virus replication linked to B cell proliferation in inflamed areas of colonic mucosa of patients with inflammatory bowel disease

BackgroundInflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract. Epstein–Barr virus (EBV) infection is associated with increased disease severity in therapeutically immunosuppressed IBD patients. The role of EBV infection in patients with IBD who are unresponsive to medical therapy is unclear. Anti-viral strategies may be a viable treatment option if severity of EBV infection, reflected in peripheral blood, contributes to IBD progression.ObjectivesWe investigated the role of EBV in IBD patients unresponsive to medical therapy by examining EBV reactivation and B-cell proliferation in colonic mucosa.Study designEBV DNA copy numbers were measured by real-time PCR in peripheral blood mononuclear cells (PBMC) of 84 patients with IBD and 115 non-IBD controls in a retrospective cross-sectional study. EBV-infected cells in colonic mucosa were identified by immunohistochemistry.ResultsEBV load in PBMC was higher in patients with IBD than in non-IBD controls, especially in patients not responding to medication. Inflamed colonic mucosa of these patients had high levels of expression of lytic and latent EBV genes that localized to proliferating B-lymphocytes, which was not seen in patients responding to therapy.ConclusionsEBV replication was associated with severe IBD and mucosal inflammation. Increased proliferation and EBV infection of B-lymphocytes in inflamed colonic mucosa highlight the potential role of EBV in mucosal inflammation. The immunomodulatory effects of EBV could delay the resolution of the IBD associated inflammation, thus contributing to disease progression. These results indicate that anti-viral therapeutic strategies for the resolution of IBD may be useful.     

Interleukin 1α: a comprehensive review on the role of IL-1α in the pathogenesis and treatment of autoimmune and inflammatory diseases

The interleukin (IL)-1 family member IL-1α is a ubiquitous and pivotal pro-inflammatory cytokine. The IL-1α precursor is constitutively present in nearly all cell types in health, but is released upon necrotic cell death as a bioactive mediator. IL-1α is also expressed by infiltrating myeloid cells within injured tissues. The cytokine binds the IL-1 receptor 1 (IL-1R1), as does IL-1β, and induces the same pro-inflammatory effects. Being a bioactive precursor released upon tissue damage and necrotic cell death, IL-1α is central to the pathogenesis of numerous conditions characterized by organ or tissue inflammation. These include conditions affecting the lung and respiratory tract, dermatoses and inflammatory skin disorders, systemic sclerosis, myocarditis, pericarditis, myocardial infarction, coronary artery disease, inflammatory thrombosis, as well as complex multifactorial conditions such as COVID-19, vasculitis and Kawasaki disease, Behcet’s syndrome, Sjogren Syndrome, and cancer.This review illustrates the clinical relevance of IL-1α to the pathogenesis of inflammatory diseases, as well as the rationale for the targeted inhibition of this cytokine for treatment of these conditions. Three biologics are available to reduce the activities of IL-1α; the monoclonal antibody bermekimab, the IL-1 soluble receptor rilonacept, and the IL-1 receptor antagonist anakinra. These advances in mechanistic understanding and therapeutic management make it incumbent on physicians to be aware of IL-1α and of the opportunity for therapeutic inhibition of this cytokine in a broad spectrum of diseases.     

A new effect of IL-4 on human γδ T cells: promoting regulatory Vδ1 T cells via IL-10 production and inhibiting function of Vδ2 T cells

Interleukin 4 (IL-4) has a variety of immune functions, including helper T-cell (Th-cell) differentiation and innate immune-response processes. However, the impact of IL-4 on gamma delta (γδ) T cells remains unclear. In this study, we investigate the effects of IL-4 on the activation and proliferation of γδ T cells and the balance between variable delta 1 (Vδ1) and Vδ2 T cells in humans. The results show that IL-4 inhibits the activation of γδ T cells in the presence of γδ T-cell receptor (TCR) stimulation in a STAT6-dependent manner. IL-4 promoted the growth of activated γδ T cells and increased the levels of Vδ1 T cells, which in turn inhibited Vδ2 T-cell growth via significant IL-10 secretion. Vδ1 T cells secreted significantly less interferon gamma (IFNγ) and more IL-10 relative to Vδ2. Furthermore, Vδ1 T cells showed relatively low levels of Natural Killer Group 2D (NKG2D) expression in the presence of IL-4, suggesting that Vδ1 T cells weaken the γδ T cell-mediated anti-tumor immune response. For the first time, our findings demonstrate a negative regulatory role of IL-4 in γδ T cell-mediated anti-tumor immunity.     

Characterization of small spheres derived from various solid tumor cell lines: are they suitable targets for T cells?

T cell based immunotherapy has been investigated in a variety of malignancies and analyses have been mostly founded on in vitro data with tumor cell monolayers. However, three-dimensional (3D) culture models might mimic more closely the ‘in vivo’ conditions than 2D monolayers. Therefore, we analyzed the expression of tumor-associated antigens (TAA) and of molecules involved in antigen processing and presentation (APM) in tumor spheres, which served as an in vitro model for micrometastasis which might be enriched in tumor propagating cancer stem cells. For enrichment of sphere cells 12 human solid tumor cell lines were cultured in serum-free medium. Expression of a variety of TAA and APM were analyzed by RT-PCR and/or flow cytometry and compared to expression in corresponding adherent bulk cells grown in regular growth medium. Compared to adherent cells, spheres showed equal or higher mRNA expression levels of LMP2, LMP7 and MECL-1, of TAP1 and TAP2 transporters and, surprisingly, also of TAA including differentiation antigens. However, downregulation or loss of HLA-I and HLA-II molecules in spheres was observed in 8 of 10 and 1 of 2 cell lines, respectively, and was unresponsive to stimulation with IFN-γ. Although tumor spheres express TAA and molecules of intracellular antigen processing, they are defective in antigen presentation due to downregulation of HLA surface expression which may lead to immune evasion.     

IL-10 signaling in dendritic cells controls IL-1β-mediated IFNγ secretion by human CD4+ T cells: relevance to inflammatory bowel disease

Uncontrolled interferon γ (IFNγ)-mediated T-cell responses to commensal microbiota are a driver of inflammatory bowel disease (IBD). Interleukin-10 (IL-10) is crucial for controlling these T-cell responses, but the precise mechanism of inhibition remains unclear. A better understanding of how IL-10 exerts its suppressive function may allow identification of individuals with suboptimal IL-10 function among the heterogeneous population of IBD patients. Using cells from patients with an IL10RA deficiency or STAT3 mutations, we demonstrate that IL-10 signaling in monocyte-derived dendritic cells (moDCs), but not T cells, is essential for controlling IFNγ-secreting CD4⁺ T cells. Deficiency in IL-10 signaling dramatically increased IL-1β release by moDCs. IL-1β boosted IFNγ secretion by CD4⁺ T cells either directly or indirectly by stimulating moDCs to secrete IL-12. As predicted a signature of IL-10 dysfunction was observed in a subgroup of pediatric IBD patients having higher IL-1β expression in activated immune cells and macroscopically affected intestinal tissue. In agreement, reduced IL10RA expression was detected in peripheral blood mononuclear cells and a subgroup of pediatric IBD patients exhibited diminished IL-10 responsiveness. Our data unveil an important mechanism by which IL-10 controls IFNγ-secreting CD4⁺ T cells in humans and identifies IL-1β as a potential classifier for a subgroup of IBD patients.     

A case of aberrant CD8 T cell–restricted IL-7 signaling with a Janus kinase 3 defect–associated atypical severe combined immunodeficiency

Immunologic Research - Severe combined immunodeficiency (SCID) disorders compromise lymphocyte numbers and/or function. One subset of SCID typically affects T cell and Natural Killer (NK) cell...     

The GM–CSF/IL-3/IL-5 cytokine receptor family: from ligand recognition to initiation of signaling

Granulocyte–macrophage colony-stimulating factor (GM–CSF), interleukin-3 (IL-3), and IL-5 are members of a discrete family of cytokines that regulates the growth, differentiation, migration and effector function activities of many hematopoietic cells and immunocytes. These cytokines are involved in normal responses to infectious agents, bridging innate and adaptive immunity. However, in certain cases, the overexpression of these cytokines or their receptors can lead to excessive or aberrant initiation of signaling resulting in pathological conditions, with chronic inflammatory diseases and myeloid leukemias the most notable examples. Recent crystal structures of the GM–CSF receptor ternary complex and the IL-5 binary complex have revealed new paradigms of cytokine receptor activation. Together with a wealth of associated structure–function studies, they have significantly enhanced our understanding of how these receptors recognize cytokines and initiate signals across cell membranes. Importantly, these structures provide opportunities for structure-based approaches for the discovery of novel and disease-specific therapeutics. In addition, recent biochemical evidence has suggested that the GM–CSF/IL-3/IL-5 receptor family is capable of interacting productively with other membrane proteins at the cell surface. Such interactions may afford additional or unique biological activities and might be harnessed for selective modulation of the function of these receptors in disease.     

High-content imaging and gene expression analysis to study cell–nanomaterial interactions: The effect of surface hydrophobicity

The effects of nanoparticle (NP)-related parameters on cellular interactions are currently uncertain as analysis is complicated by the combinatorial diversity arising from the array of size, shape and surface properties. Here, we present a validated multiparametric high-content imaging method, with the utility of this approach demonstrated by in-depth analysis of the role of hydrophobicity on the interaction of Au NPs with cultured cells. In this methodology, we evaluate cell viability, membrane damage, induction of reactive oxygen species, mitochondrial health, cell area, skewness and induction of autophagy. High-content cell cycle phase studies and in-depth gene expression studies then serve to elucidate the underlying mechanisms. The data reveal a clear influence of the degree of NP surface hydrophobicity with membrane damage and autophagy induction, which is stronger than the effect of surface charge, for charges ranging between −50 and +20 mV. All labeling experiments occur in the same format, and can be further supplemented with additional parameters providing a broadly accessible format for studying cell-NP interactions under highly reproducible conditions.