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Background: The phosphodiesterase 4 (PDE4) inhibitor apremilast downregulates the production of IL-23 and other pro-inflammatory cytokines involved in the pathogenesis of psoriatic arthritis (PsA). Aim: To investigate the effects of apremilast on the production of cytokines by peripheral blood monocyte-derived macrophages, innate-like lymphocyte cells (ILCs), mucosal-associated invariant T (MAIT) cells, γδ T cells, natural killer (NK) cells, and NKT-like cells from patients with PsA manifesting different clinical responses to the treatment. Methods: Peripheral blood samples were obtained from patients with PsA at baseline and after 1 and 4 months of apremilast therapy (n = 23) and 20 controls with osteoarthritis. Cytokine expression in peripheral blood monocyte-derived macrophages and ILCs/MAIT/γδT/NK/NKT-like cells was tested by RT-PCR and FACS analyses, respectively; cytokine levels in culture supernatants and sera were analyzed by ELISA. Results: PsA monocyte-derived macrophages exhibited higher expressions of IL-23, IL-1β, and TNF-α, compared with OA controls, more profoundly in patients responding to apremilast. There were 17/23 (74%) PsA patients who were classified as responders to apremilast at 4 months, and a baseline serum IL-23 >1.4 pg/mL was associated with the responder status (AUCROC 0.79; sensitivity 100%, specificity 68%). Of note, apremilast led to a significantly reduced expression of IL-23 in peripheral blood monocyte-derived macrophages; IL-17 in ILC1 and in T cells of responder patients; IFN-γ in γδ T lymphocytes. Conclusion: An enhanced myeloid inflammatory signature characterizes PsA monocyte-derived macrophages, and serum IL-23 levels represent candidate biomarkers for PsA response to apremilast. [ABSTRACT FROM AUTHOR]

BackgroundThe phosphodiesterase 4 (PDE4) inhibitor apremilast downregulates the production of IL-23 and other pro-inflammatory cytokines involved in the pathogenesis of psoriatic arthritis (PsA).AimTo investigate the effects of apremilast on the production of cytokines by peripheral blood monocyte-derived macrophages, innate-like lymphocyte cells (ILCs), mucosal-associated invariant T (MAIT) cells, γδ T cells, natural killer (NK) cells, and NKT-like cells from patients with PsA manifesting different clinical responses to the treatment.MethodsPeripheral blood samples were obtained from patients with PsA at baseline and after 1 and 4 months of apremilast therapy (n = 23) and 20 controls with osteoarthritis. Cytokine expression in peripheral blood monocyte-derived macrophages and ILCs/MAIT/γδT/NK/NKT-like cells was tested by RT-PCR and FACS analyses, respectively; cytokine levels in culture supernatants and sera were analyzed by ELISA.ResultsPsA monocyte-derived macrophages exhibited higher expressions of IL-23, IL-1β, and TNF-α, compared with OA controls, more profoundly in patients responding to apremilast. There were 17/23 (74%) PsA patients who were classified as responders to apremilast at 4 months, and a baseline serum IL-23 >1.4 pg/mL was associated with the responder status (AUCROC 0.79; sensitivity 100%, specificity 68%). Of note, apremilast led to a significantly reduced expression of IL-23 in peripheral blood monocyte-derived macrophages; IL-17 in ILC1 and in T cells of responder patients; IFN-γ in γδ T lymphocytes.ConclusionAn enhanced myeloid inflammatory signature characterizes PsA monocyte-derived macrophages, and serum IL-23 levels represent candidate biomarkers for PsA response to apremilast.

Mucosal-associated invariant T (MAIT) cells are a subset of innate-like lymphocytes that are restricted by major histocompatibility complex-related molecule 1 (MR1). In this study, we investigated the role of MAIT cells in the pathogenesis of lupus in FcγRIIb−/−Yaa mice, a spontaneous animal model of lupus. Using two approaches of MAIT cell deficiency, MR1 knockout animals and a newly synthesized inhibitory MR1 ligand, we demonstrate that MAIT cells augment the disease course of lupus by enhancing autoantibody production and tissue inflammation. MR1 deficiency reduced germinal center responses and T cell responses in these mice. Suppression of MAIT cell activation by the inhibitory MR1 ligand reduced autoantibody production and lupus nephritis in FcγRIIb−/−Yaa mice. MAIT cells directly enhanced autoantibody production by B cells in vitro. Our results indicate the contribution of MAIT cells to lupus pathology and the potential of these cells as novel therapeutic targets for autoimmune diseases such as lupus.

Mucosal-associated invariant T (MAIT) cells are a subset of innate-like lymphocytes that are restricted by major histocompatibility complex-related molecule 1 (MR1). In this study, we investigated the role of MAIT cells in the pathogenesis of lupus in FcγRIIb−/− Yaa mice, a spontaneous animal model of lupus. Using two approaches of MAIT cell deficiency, MR1 knockout animals and a newly synthesized inhibitory MR1 ligand, we demonstrate that MAIT cells augment the disease course of lupus by enhancing autoantibody production and tissue inflammation. MR1 deficiency reduced germinal center responses and T cell responses in these mice. Suppression of MAIT cell activation by the inhibitory MR1 ligand reduced autoantibody production and lupus nephritis in FcγRIIb−/− Yaa mice. MAIT cells directly enhanced autoantibody production by B cells in vitro. Our results indicate the contribution of MAIT cells to lupus pathology and the potential of these cells as novel therapeutic targets for autoimmune diseases such as lupus. [ABSTRACT FROM AUTHOR]

Lymphocytes are an integral component of the immune system. Classically, all lymphocytes were thought to perpetually recirculate between secondary lymphoid organs and only traffic to non-lymphoid tissues upon activation. In recent years, a diverse family of non-circulating lymphocytes have been identified. These include innate lymphocytes, innate-like T cells and a subset of conventional T cells. Spanning the innate-adaptive spectrum, these tissue-resident lymphocytes carry out specialized functions and cross-talk with other immune cell types to maintain tissue integrity and homeostasis both at the steady state and during pathological conditions. In this review, we provide an overview of the heterogeneous tissue-resident lymphocyte populations, discuss their development, and highlight their functions both in the context of microbial infection and cancer.

IL-17 protects against pathogens by acting on nonhematopoietic cells to induce neutrophil recruitment through upregulation of chemokines and G-CSF. IL-17- and Th17-deficient humans and mice are susceptible to mucosal Candida albicans infections, linked to impaired neutrophil responses. IL-17 production is traditionally associated with CD4+ Th17 cells. However, IL-17 is also expressed during innate responses to facilitate rapid pathogen clearance. Innate IL-17-expressing cells include various lymphocyte-type subsets, including ILC3, NKT, γδ-T and “natural” Th17 (nTh17) cells. Some reports suggest that neutrophils can express IL-17 during fungal infections. Here, we asked whether neutrophils serve as a source of IL-17 during acute oropharyngeal candidiasis (OPC) using an IL-17A fate-tracking reporter mouse. Mice were subjected to OPC for two days, and oral tissue was analyzed by flow cytometry. IL-17A was expressed by γδ-T cells and TCRβ+ natural Th17 (nTh17) cells, as recently reported. Although infiltrating neutrophils were recruited to the tongue following infection, they did not express the IL-17A reporter. Moreover, neutrophil-depleted mice exhibited normal transcription of both Il17a and downstream IL-17-dependent gene targets after Candida challenge. Thus, in acute OPC, neutrophils are not a measurable source of IL-17 production, nor are they necessary to trigger IL-17-dependent gene expression, although they are essential for ultimate pathogen control.

Asthma is a common chronic respiratory disease in which epithelial cytokines and airway inflammation play critical pathophysiological roles. Thymic stromal lymphopoietin (TSLP), an epithelial cytokine, is central in the initiation and persistence of airway inflammation in asthma. Tezepelumab is a human immunoglobulin G2λ (IgG2λ) monoclonal antibody developed for treating moderate-to-severe asthma by specifically binding to TSLP and preventing its binding to the TSLP receptor on inflammatory cells. In this narrative review, we describe the results of clinical trials that evaluated the pharmacokinetics, pharmacodynamics, efficacy and safety of tezepelumab in patients with moderate-to-severe asthma. We also introduce the ongoing clinical trials in patients with asthma as well as future trials investigating the use of tezepelumab for other indications.

The adaptive immune system, composed of lymphocytes, recognizes diversified antigens and generates immunological memory. According to the canonical model, it is the innate immune system that captures pathogens and senses environment to activate adaptive lymphocytes through antigen presentation, costimulatory signals and cytokine milieu. Emerging evidence indicates that environmental cues can be directly conveyed to lymphocytes by the aryl hydrocarbon receptor (AhR). AhR is a ligand-activated transcription factor that widely expresses in many immune cell lineages and recognizes a broad range of ligands including endogenous and dietary metabolites, microbial derivatives and xenobiotics. This review will focus on the regulatory role of AhR in not only adaptive but also innate lymphocytes including recently discovered innate lymphoid cells. [ABSTRACT FROM AUTHOR]

Production of innate interferon-gamma(IFN-gamma) is a crucial step in immunological defense against bacteria. However, there is little information regarding cellular mechanisms underlying IFN-gamma production in vivo early after bacterial infection. Here we analyze innate-IFN-gamma production in the spleen of mice early after Listeria monocytogenes (LM) infection ex vivo by flow-cytometry and in situ by immunohistochemisrty, and compare them with the IFN-gamma-producing cells reported previously in our in vitro coculture system in which cell-cell interaction between lymphocytes and dying bacterial-infected macrophages is required for the production of IFN-gamma. In the spleen at 20 h after LM infection, natural killer (NK) cells, a subset of alpha/beta T cells, and subsets of NKT and gamma/delta T cells produced IFN-gamma with features similar to the IFN-gamma-producing cells in our in vitro coculture system. Immunohistochemistry revealed that LM bacteria were first phagocytosed mainly by ER-TR9+ marginal-zone macrophages (MZMs), then forming infectious foci in close vicinity of the marginal zone (MZ) at 20-h postinfection. At this time point, the IFN-gamma-producing cells were accumulating at the same site of infectious foci, around which ER-TR9+ MZMs were clustered but most of bacteria were no longer associated with ER-TR9+ MZMs. These results indicate that innate-IFN-gamma production by innate lymphocytes takes place at infectious foci formed in close vicinity of the MZ, and they also suggest an important role for the microenvironment of the cells accumulated at infectious foci in inducing the production of innate IFN-gamma.

• Bacillus anthracis edema toxin (ET), a potent adenylate cyclase, induces IL-22 in MNK-3 cells, a mouse ILC3-like cell line. • Forskolin, another cAMP elevating agent, also induces IL-22 in MNK-3 cells. • Forskolin and IL-1β induce CREB phosphorylation in MNK-3 cells. Group 3 innate lymphocytes (ILC3s) are important immune cells within mucosal tissues and protect against bacterial infections. They can be activated in response to the innate cytokines IL-23 or IL-1β, which rapidly increases their production of effector molecules that regulate barrier functions. Pathogens can subvert these anti-bacterial effects to evade mucosal defenses to infect the host. Bacillus anthracis , the causative agent of anthrax, produces two major toxins that can modulate the immune response. We have previously shown that lethal toxin downmodulates the function of ILC3s. On the other hand, edema toxin has been shown promote T helper 17 (Th17) cell differentiation, adaptive counterparts of ILC3s, via elevation of cyclic adenosine monophosphate (cAMP). We hypothesized that edema toxin may also modulate ILC3 function. In this study, we show that edema toxin has the opposite effect of lethal toxin; edema toxin directly activates ILC3s independently of innate cytokine stimulation. Treatment of a mouse ILC3-like cell line with edema toxin, a potent adenylate cyclase, upregulated production of the cytokine IL-22, a major effector molecule of ILC3s and a critical factor in maintaining mucosal barriers. Forskolin treatment phenocopied the effect observed with edema toxin and led to an increase in CREB phosphorylation in ILC3s. This observation has potential implications for a role for cAMP signaling in the activation of ILC3s. [ABSTRACT FROM AUTHOR]

ABSTRACT Murine γδ T cells develop as the first T-cell lineage within the fetal thymus and disproportionately localize in mucosal tissues such as lung, skin, uterus, and intestine of adult mice. These unique developmental features and distribution patterns of γδ T cells enable rapid functioning against various insults from pathogens. γδ T cells are also able to respond to local inflammation and consequently regulate the pathogenesis of autoimmune disorders and development of tumors in mice and humans. Hence, it is clinically important to understand the mechanisms that regulate γδ T cell functions. Recent evidence has shown that generations of effector γδ T cell subsets producing IFN-γ, IL-4, and IL-17 are programmed in the murine thymus before their migration to peripheral tissues. This review outlines our current understanding of the development and function of γδ T cells as they influence both innate and acquired immunity. [ABSTRACT FROM AUTHOR]

Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium -reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of Mycobacterium -non reactive classic T H 1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8+ αβ T and non-classic CD4+ αβ T H 1∗ lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8+ αβ T, and CD4+ αβ T H 1∗ cells unable to compensate for this deficit. • Human inherited T-bet deficiency underlies severe mycobacterial disease • The development of a variety of IFN-γ-producing lymphocyte subsets is impaired • The production of IFN-γ by innate and innate-like lymphocytes is impaired • Mycobacterium -specific αβ CD4 T H 1∗ and CD8 cells produce IFN-γ normally Human T-bet is involved in the regulation of distinct leukocyte subsets, when compared with its mouse counterpart, with its deficiency underlying severe mycobacterial disease [ABSTRACT FROM AUTHOR]

Group 2 innate lymphoid cells (ILC2) have emerged as a major component of type 2 inflammation in mice and humans. ILC2 secrete large amounts of interleukins 5 and 13, which are largely responsible for host protective immunity against helminth parasites because these cytokines induce profound changes in host physiology that include: goblet cell metaplasia, mucus accumulation, smooth muscle hypercontractility, eosinophil and mast cell recruitment, and alternative macrophage activation (M2). This review covers the initial recognition of ILC2 as a distinct cell lineage, the key studies that established their biological importance, particularly in helminth infection, and the new directions that are likely to be the focus of emerging work that further explores this unique cell population in the context of health and disease. [ABSTRACT FROM AUTHOR]

Lymphocytes are an integral component of the immune system. Classically, all lymphocytes were thought to perpetually recirculate between secondary lymphoid organs and only traffic to non-lymphoid tissues upon activation. In recent years, a diverse family of non-circulating lymphocytes have been identified. These include innate lymphocytes, innate-like T cells and a subset of conventional T cells. Spanning the innate-adaptive spectrum, these tissue-resident lymphocytes carry out specialized functions and cross-talk with other immune cell types to maintain tissue integrity and homeostasis both at the steady state and during pathological conditions. In this review, we provide an overview of the heterogeneous tissue-resident lymphocyte populations, discuss their development, and highlight their functions both in the context of microbial infection and cancer.

IL-17 protects against pathogens by acting on nonhematopoietic cells to induce neutrophil recruitment through upregulation of chemokines and G-CSF. IL-17- and Th17-deficient humans and mice are susceptible to mucosal Candida albicans infections, linked to impaired neutrophil responses. IL-17 production is traditionally associated with CD4+ Th17 cells. However, IL-17 is also expressed during innate responses to facilitate rapid pathogen clearance. Innate IL-17-expressing cells include various lymphocyte-type subsets, including ILC3, NKT, γδ-T and "natural" Th17 (nTh17) cells. Some reports suggest that neutrophils can express IL-17 during fungal infections. Here, we asked whether neutrophils serve as a source of IL-17 during acute oropharyngeal candidiasis (OPC) using an IL-17A fate-tracking reporter mouse. Mice were subjected to OPC for two days, and oral tissue was analyzed by flow cytometry. IL-17A was expressed by γδ-T cells and TCRβ+ natural Th17 (nTh17) cells, as recently reported. Although infiltrating neutrophils were recruited to the tongue following infection, they did not express the IL-17A reporter. Moreover, neutrophil-depleted mice exhibited normal transcription of both Il17a and downstream IL-17-dependent gene targets after Candida challenge. Thus, in acute OPC, neutrophils are not a measurable source of IL-17 production, nor are they necessary to trigger IL-17-dependent gene expression, although they are essential for ultimate pathogen control.

Production of innate interferon-γ (IFN-γ) is a crucial step in immunological defense against bacteria. However, there is little information regarding cellular mechanisms underlying IFN-γ production in vivo early after bacterial infection. Here we analyze innate IFN-γ production in the spleen of mice early after Listeria monocytogenes (LM) infection ex vivo by flow-cytometry and in situ by immunohistochemistry, and compare them with the IFN-γ-producing cells reported previously in our in vitro coculture system in which cell-cell interaction between lymphocytes and dying bacterial-infected macrophages is required for the production of IFN-γ. In the spleen at 20 h after LM infection, natural killer (NK) cells, a subset of αβ T cells, and subsets of NKT and γδ T cells produced IFN-γ with features similar to the IFN-γ-producing cells in our in vitro coculture system. Immunohistochemistry revealed that LM bacteria were first phagocytosed mainly by ER-TR9⁺ marginal zone macrophages (MZMs), then forming infectious foci in close vicinity of the marginal zone (MZ) at 20-h postinfection. At this time point, the IFN-γ-producing cells were accumulating at the same site of infectious foci, around which ER-TR9⁺ MZMs were clustered but most of bacteria were no longer associated with ER-TR9⁺ MZMs. These results indicate that innate IFN-γ production by innate lymphocytes takes place at infectious foci formed in close vicinity of the MZ, and they also suggest an important role for the microenvironment of the cells accumulated at infectious foci in inducing the production of innate IFN-γ.