An understanding of interactions within the tumor microenvironment (TME) of classic Hodgkin Lymphoma (cHL) has helped pave the way to novel immunotherapies that have enabled dormant and tumor-tolerant immune cells to be reactivated. The immunosuppressive nature of the TME in cHL specifically inhibits the proliferation and activity of Natural Killer (NK) cells, which contributes to tumor immune escape mechanisms. This deficiency of NK cells begins at the tumor site and progresses systemically in patients with advanced disease or adverse prognostic factors. Several facets of cHL account for this effect on NK cells. Locally, malignant Reed-Sternberg cells and cells from the TME express ligands for inhibitory receptors on NK cells, including HLA-E, HLA-G, and PD-L1. The secretion of chemokines and cytokines, including soluble IL-2 receptor (sCD25), TGF-ß, IL-10, CXCL-9, and CXCL-10, mediate the systemic immunosuppression. This review also discusses the potential reversibility of quantitative and functional NK cell deficiencies in cHL that are likely to lead to novel treatments.
Obesity is associated with chronic inflammation and accumulation of immune cells in adipose tissue. Here, Wilson et al . report that macrophages that express neuropilin-1 (NRP1) play an essential role in limiting obesity-associated inflammation. In mice placed on a high-fat diet, deletion of NRP1 in myeloid cells accelerated both weight gain and development of insulin resistance. The authors found that NRP1 regulated fatty acid uptake in macrophages and that deficiency of NRP1 skewed their metabolism toward glycolysis, which is associated with a more aggressive inflammation. The studies add to the growing recognition of the importance of immune cells in obesity and other metabolic syndromes.
Germinal centers (GCs) are the sites where B cells undergo affinity maturation. The regulation of cellular output from the GC is not well understood. Here, we show that from the earliest stages of the GC response, plasmablasts emerge at the GC–T zone interface (GTI). We define two main factors that regulate this process: Tfh-derived IL-21, which supports production of plasmablasts from the GC, and TNFSF13 (APRIL), which is produced by a population of podoplanin+ CD157high fibroblastic reticular cells located in the GTI that are also rich in message for IL-6 and chemokines CXCL12, CCL19, and CCL21. Plasmablasts in the GTI express the APRIL receptor TNFRSF13B (TACI), and blocking TACI interactions specifically reduces the numbers of plasmablasts appearing in the GTI. Plasma cells generated in the GTI may provide an early source of affinity-matured antibodies that may neutralize pathogens or provide feedback regulating GC B cell selection.
Il10 forms a cytokine cluster with Il19 , Il20 , and Il24 in a conserved region of chromosome 1. The latter genes are in the IL-20 subfamily of IL-10–related cytokines and, although they are not as well studied their biologic actions and expression patterns, seem to have little in common with IL-10. IL-24, like IL-10, however, is uniquely expressed in T cells and is a signature gene of the Th2 lineage, which suggests they could be coregulated in certain cell types. Little is known about other cellular sources of IL-24. We investigated IL-24 and IL-10 expression in murine macrophages and NK cells, and found that although they are coexpressed under most stimulation conditions, IL-24 and IL-10 are controlled by distinct, cell type–specific pathways. In bone marrow–derived macrophages, optimal IL-24 expression required LPS+IL-4 costimulation and STAT6 but was independent of type I IFN receptor signaling and STAT4. Conversely, LPS-induced IL-10 was independent of IL-4/STAT6 and STAT4 but, consistent with other reports, required type I IFN receptor signaling for optimal expression. Remarkably, NK-specific IL-24 (but not IL-10) expression was dependent on both type I IFN receptor signaling and STAT4. Induction of IL-24 expression was accompanied by cell-specific recruitment of STAT6 and STAT4 to multiple sites that we identified within Il24 , which mediated STAT-dependent histone modifications across the gene. Collectively, our results indicate that despite being coexpressed, IL-10 and IL-24 are independently regulated by different type I IFN receptor signaling pathways in innate immune cells and provide insight into the mechanisms that fine-tune cell type–specific gene expression within the Il10 cluster.
CD4+ Th cells can have cytotoxic activity against cells displaying relevant peptide-MHC class II (p:MHCII) ligands. Cytotoxicity may be a property of Th1 cells and depends on perforin and the Eomes transcription factor. We assessed these assertions for polyclonal p:MHCII-specific CD4+ T cells activated in vivo in different contexts. Mice immunized with an immunogenic peptide in adjuvant or infected with lymphocytic choriomeningitis virus or Listeria monocytogenes bacteria induced cytotoxic Th cells that killed B cells displaying relevant p:MHCII complexes. Cytotoxicity was dependent on Fas expression by target cells but was independent of Eomes or perforin expression by T cells. Although the priming regimens induced different proportions of Th1, Th17, regulatory T cells, and T follicular helper cells, the T cells expressed Fas ligand in all cases. Reciprocally, Fas was upregulated on target cells in a p:MHCII-specific manner. These results indicate that many Th subsets have cytotoxic potential that is enhanced by cognate induction of Fas on target cells.
Immune-Responsive Gene 1 (Irg1) is a mitochondrial enzyme that produces itaconate under inflammatory conditions, principally in cells of myeloid lineage. Cell culture studies suggest that itaconate regulates inflammation through its inhibitory effects on cytokine and reactive oxygen species production. To evaluate the functions of Irg1 in vivo, we challenged wild-type (WT) and Irg1 −/− mice with Mycobacterium tuberculosis ( Mtb ) and monitored disease progression. Irg1 −/−, but not WT, mice succumbed rapidly to Mtb , and mortality was associated with increased infection, inflammation, and pathology. Infection of LysM -Cre Irg1 fl/fl, Mrp8 -Cre Irg1 fl/fl, and CD11c -Cre Irg1 fl/fl conditional knockout mice along with neutrophil depletion experiments revealed a role for Irg1 in LysM + myeloid cells in preventing neutrophil-mediated immunopathology and disease. RNA sequencing analyses suggest that Irg1 and its production of itaconate temper Mtb -induced inflammatory responses in myeloid cells at the transcriptional level. Thus, an Irg1 regulatory axis modulates inflammation to curtail Mtb -induced lung disease.
CD4+ Th cell differentiation is crucial for protecting against blood-stage Plasmodium parasites, the causative agents of malaria. It has been known for decades that more than one type of Th cell develops during this infection, with early models proposing a biphasic Th1/Th2 model of differentiation. Over the past decade, a large body of research, in particular, reports over the past 2–3 y, have revealed substantial complexity in the Th differentiation program during Plasmodium infection. In this article, we review how several studies employing mouse models of malaria, and recent human studies, have redefined the process of Th differentiation, with a particular focus on Th1 and T follicular helper (Tfh) cells. We review the molecular mechanisms that have been reported to modulate Th1/Tfh differentiation, and propose a model of Th1/Tfh differentiation that accommodates observations from all recent murine and human studies.
The immunoregulatory and anti-infective properties of normal circulating polyclonal Abs have been exploited for the therapeutic purposes in the form of IVIG as well as several hyperimmune globulins. Current knowledge on the therapeutic use of normal Igs is based on the discoveries made by several pioneers of the field. In this paper, we review the evolution of IVIG over the years. More importantly, the process started as an s.c. replacement in γ globulin–deficient patients, underwent metamorphosis into i.m. Ig, was followed by IVIG, and is now back to s.c. forms. Following successful use of IVIG in immune thrombocytopenic purpura, there has been an explosion in the therapeutic applications of IVIG in diverse autoimmune and inflammatory conditions. In addition to clinically approved pathological conditions, IVIG has been used as an off-label drug in more than 100 different indications. The current worldwide consumption of IVIG is over 100 tons per year.
Immune responses are critical for the maintenance of homeostasis but can also upset the equilibrium, depending on the context and magnitude of the response. Natural killer (NK) cells are well known for their important roles in antiviral and antitumor immune responses, and they are currently used, mostly under optimized forms, as immunotherapeutic agents against cancer. Nevertheless, with accumulating examples of deleterious effects of NK cells, it is paramount to consider their negative contributions.
Triple III By ATS Created by Mathew Currie, Shalisha Maisrikrod & Natkunam Ketheesan. A collaborative production by Australian Tropical Solutions and One
The way in which immune cells recognize their targets has long been a subject of intense research in the immunological community. The discovery of Abs and identification of the TCR attest to the excitement surrounding this subject. However, the unique and beautiful nature of the mechanisms
The activating immune receptor natural killer group 2 member D (NKG2D), which is expressed by NK cells and T cell subsets, recognizes a number of ligands expressed by “stressed” or damaged cells. NKG2D has been extensively studied for its role in tumor immunosurveillance and anti-viral immunity. To date, the majority of studies have focused on NKG2D-mediated killing of target cells expressing NKG2D ligands. However, with a number of reports describing expression of NKG2D ligands by cells that are not generally considered stressed, it is becoming clear that some healthy cells also express NKG2D ligands. Expression of these ligands by cells within the skin, intestinal epithelium, and the immune system suggest other immune functions for NKG2D ligand expression in addition to its canonical role as a “kill me” signal. How NKG2D ligands function in this capacity is just now starting to be unraveled. In this review we examine the expression of NKG2D ligands by immune cells and discuss current literature describing the effects of this expression on immunity and immune regulation.
GATA-binding protein 3 (GATA3) acts as the master transcription factor for type 2 T helper (Th2) cell differentiation and function. However, it is still elusive how GATA3 function is precisely regulated in Th2 cells. Here, we show that the transcription factor B cell lymphoma 11b (Bcl11b), a previously unknown component of GATA3 transcriptional complex, is involved in GATA3-mediated gene regulation. Bcl11b binds to GATA3 through protein–protein interaction, and they colocalize at many important cis-regulatory elements in Th2 cells. The expression of type 2 cytokines, including IL-4, IL-5, and IL-13, is up-regulated in Bcl11b -deficient Th2 cells both in vitro and in vivo; such up-regulation is completely GATA3 dependent. Genome-wide analyses of Bcl11b- and GATA3-regulated genes (from RNA sequencing), cobinding patterns (from chromatin immunoprecipitation sequencing), and Bcl11b-modulated epigenetic modification and gene accessibility suggest that GATA3/Bcl11b complex is involved in limiting Th2 gene expression, as well as in inhibiting non-Th2 gene expression. Thus, Bcl11b controls both GATA3-mediated gene activation and repression in Th2 cells.
Glucocorticoid (GC) signaling in thymocytes counters negative selection and promotes the generation of a self-tolerant yet Ag-responsive T cell repertoire. Whereas circulating GC are derived from the adrenals, GC are also synthesized de novo in the thymus. The significance of this local production is unknown. In this study we deleted 11β-hydroxylase, the enzyme that catalyzes the last step of GC biosynthesis, in thymic epithelial cells (TEC) or thymocytes. Like GC receptor–deficient T cells, T cells from mice lacking TEC-derived but not thymocyte-derived GC proliferated poorly to alloantigen, had a reduced antiviral response, and exhibited enhanced negative selection. Strikingly, basal expression of GC-responsive genes in thymocytes from mice lacking TEC-derived GC was reduced to the same degree as in GC receptor–deficient thymocytes, indicating that at steady-state the majority of biologically active GC are paracrine in origin. These findings demonstrate the importance of extra-adrenal GC even in the presence of circulating adrenal-derived GC.
The T-box transcription factors T-bet and Eomesodermin (Eomes) instruct discrete stages in NK cell development. However, their role in the immune response of mature NK cells against pathogens remains unexplored. We used an inducible deletion system to elucidate the cell-intrinsic role of T-bet and Eomes in mature NK cells during the course of mouse CMV infection. We show both T-bet and Eomes to be necessary for the expansion of virus-specific NK cells, with T-bet upregulation induced by IL-12 signaling and STAT4 binding to a conserved enhancer region upstream of the Tbx21 loci. Interestingly, our data suggest maintenance of virus-specific memory NK cell numbers and phenotype was dependent on T-bet, but not Eomes. These findings uncover a nonredundant and stage-specific influence of T-box transcription factors in the antiviral NK cell response.
Des chercheurs marseillais ont observé comment le pigment persistait indéfiniment alors que les cellules de la peau mouraient. Ce qui pourrait servir à faciliter la suppression des tatouages.
Nuclear factor of activated T cells (NFAT) was first described almost three decades ago as a Ca2+/calcineurin-regulated transcription factor in T cells. Since then, a large body of research uncovered the regulation and physiological function of different NFAT homologues in the immune system and many other tissues. In this review, we will discuss novel roles of NFAT in T cells, focusing mainly on its function in humoral immune responses, immunological tolerance, and the regulation of immune metabolism.
Sepsis results in a deluge of pro- and anti-inflammatory cytokines, leading to lymphopenia and chronic immunoparalysis. Sepsis-induced long-lasting immunoparalysis is defined, in part, by impaired CD4 and CD8 αβ T cell responses in the postseptic environment. The dysfunction in T cell immunity affects naive, effector, and memory T cells and is not restricted to classical αβ T cells. Although sepsis-induced severe and transient lymphopenia is a contributory factor to diminished T cell immunity, T cell–intrinsic and -extrinsic factors/mechanisms also contribute to impaired T cell function. In this review, we summarize the current knowledge of how sepsis quantitatively and qualitatively impairs CD4 and CD8 T cell immunity of classical and nonclassical T cell subsets and discuss current therapeutic approaches being developed to boost the recovery of T cell immunity postsepsis induction.
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