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Innate lymphoid cells (ILCs) mainly reside at barrier surfaces and regulate tissue homeostasis and immunity. ILCs are divided into 3 groups, group 1 ILCs, group 2 ILCs, and group 3 ILC3, on the basis of their similar effector programs to T cells. The development of ILCs from lymphoid progenitors in adult mouse bone marrow has been studied in detail, and multiple ILC progenitors have been characterized. ILCs are mostly tissue-resident cells that develop in the perinatal period. More recently, ILC progenitors have also been identified in peripheral tissues. In this review, we discuss the stepwise transcription factor–directed differentiation of mouse ILC progenitors into mature ILCs, the critical time windows in ILC development, and the contribution of bone marrow versus tissue ILC progenitors to the pool of mature ILCs in tissues. [ABSTRACT FROM AUTHOR]

Summary All lymphocytes are thought to develop from common lymphoid progenitors (CLPs). However, lymphoid-primed multipotent progenitors (LMPPs) are more efficient than CLPs in differentiating into T cells and group 2 innate lymphoid cells (ILC2s). Here, we have divided LMPPs into CD127 − (LMPP−s) and CD127 + (LMPP+s) subsets and compared them with Ly6D − and Ly6D + CLPs. Adult LMPP+s differentiated into T cells and ILCs more rapidly and efficiently than other progenitors in transplantation assays. The development of T cells and ILC2s is highly active in the neonatal period. Neonatal CLPs are rare and, unlike prominent neonatal LMPP+s, do not efficiently differentiate into T cells and ILC2s. ILC2s generated in the neonatal period are long lived and persist in adult tissues. These results suggest that some ILCs and T cells may develop from LMPP+s via CLP-independent pathways. [ABSTRACT FROM AUTHOR]

Expanding highly cytotoxic lymphokine activated natural killer cells and cytokine induced killer T cells by Good Manufacturing Practice-quality cultures is an important step toward effective use of those killer cells to treat acute myeloid leukemia patients receiving stem cell transplantation. Elucidating how those killer cells recognize leukemia stem cells will be the next challenge. [ABSTRACT FROM AUTHOR]

Background: Allergic inflammation involves the sensitization of naive CD4+ T cells to allergens, resulting in a TH2-skewed inflammatory response. Although antigen presentation by dendritic cells to T cells in the lymph node is crucial for TH2 cell development, the innate signals that initiate adaptive type 2 inflammation and the role of group 2 innate lymphoid cells (ILC2s) are poorly understood. Objective: We sought to investigate the influence of ILC2s and the route of priming on the development of an adaptive type 2 immune response to lung allergens. Methods: Wild-type and ILC2-deficient mice were exposed intranasally or systemically to the TH2-inducing antigens house dust mite or ovalbumin in a model of allergic airway inflammation or the TH17-inducing bacterial antigen Saccharopolyspora rectivirgula in a model of hypersensitivity pneumonitis. The formation of an adaptive immune response was evaluated based on serum antibody titers and production of T cell–derived cytokines (IL-4, IL-5, IL-13 and IL-17A). Results: We find that lung ILC2s play a critical role in priming the adaptive type 2 immune response to inhaled allergens, including the recruitment of eosinophils, TH2 cytokine production and serum IgE levels. Surprisingly, systemic priming with ovalbumin, with or without adjuvants, circumvents the requirement for ILC2s in inducing TH2-driven lung inflammation. ILC2s were also found to be dispensable for the sensitization to TH1- or TH17-inducing antigens. Conclusion: These data highlight a critical role for ILC2s in the development of adaptive type 2 responses to local, but not systemic, antigen exposure. [Copyright &y& Elsevier]

How allergens trigger the T helper 2 (Th2) response that characterizes allergic lung inflammation is not well understood. Epithelium-derived alarmins released after an allergen encounter activate the innate immune system, including group 2 innate lymphoid cells (ILC2s) which produce the type 2 interleukins IL-5 and IL-13. It has been recently shown that ILC2-derived cytokines are responsible not only for the innate responses underlying allergic inflammation but also for the initiation of the adaptive Th2 response. We review the role of lung ILC2s in the development of allergic inflammation and, in the context of recent findings, propose a common pathway wherein ILC2s, activated by the epithelium-derived cytokine IL-33, link the innate and the adaptive responses after allergen encounter in the lung. [ABSTRACT FROM AUTHOR]

We have identified a population of normal mouse LN cells, termed LN lymphoid progenitor (LNLP), resembling common lymphoid progenitor (CLP) in the bone marrow. LNLPs lack lineage markers and express CD127, low levels of CD117 (c-Kit), and Sca-1, but lack fms-related tyrosine kinase 3. They efficiently differentiate in vitro into natural killer (NK) cells and T cells, but not mature B cells. LNLPs injected into nonirradiated lymphopenic mice that have no LN develop into mostly splenic T cells with low numbers of NK cells and B cells. When injected into irradiated mice, they generate NK cells and T cells, but not B cells, in the LN. By contrast, bone marrow CLPs develop into mostly B cells with very small numbers of T and NK cells in recipients’ spleen and LN. LNLPs have NK and T-cell potentials, but little B-cell potential, and they can develop into NK cells within the LN of normal mice, but their contribution to the T-cell lineage is unknown. [ABSTRACT FROM AUTHOR]

Abstract: The predominant NK receptors recognizing MHC class I molecules are encoded by the killer cell immunoglobulin-like (KIR) genes in primates and the Ly49 genes in rodents. In human NK cells, the KIR repertoire is maintained epigenetically at the level of transcription via DNA methylation of the promoter region. We have previously shown a role for epigenetic mechanisms in the control of Ly49a transcription. However, it is unknown if all Ly49 genes are similarly regulated as they are diverged from each other in both DNA sequence and expression pattern. Ly49G is unstably expressed on EL4-derived sublines; some sublines lack expression while others such as RMA-E3 have substantial but variable expression. Here we show that transcription from the Pro-2 promoter of Ly49g is activated in an Ly49G-non-expressing EL4 subline after treatment with the histone deacetylase inhibitor, trichostatin-A. Ly49Ghigh RMA-E3 cells have significant hyperacetylation of the Pro-2 region compared to Ly49G− lymphoid and non-lymphoid cell lines. We hypothesize that the variable histone acetylation state at the Pro-2 region of Ly49g is responsible for the unstable and variable expression of Ly49G in the EL4 and RMA NKT cell lines. Histone acetylation may be the main epigenetic mechanism of transcriptional regulation for Ly49g in lymphoid cell lines and primary NK cells. [Copyright &y& Elsevier]

Immunological memory has long been described as a property of the adaptive immune system that results in potent responses on exposure to an antigen encountered previously. While this definition appears to exclude cells that do not express antigen receptors, recent studies have shown that innate immune cells, including natural killer (NK) cells, macrophages, and, more recently, group 2 innate lymphoid cells (ILC2s) can record previous activations and respond more vigorously on reactivation. Here we review the similarities and differences between these forms of memory and the underlying mechanisms. Based on these insights, we propose to revise the definition of immunological memory, as the capacity to remember being previously activated and respond more efficiently on reactivation regardless of antigen specificity. [ABSTRACT FROM AUTHOR]

: ObjectiveAdult mouse natural killer (NK) cells express two families of MHC class I–specific receptors, namely Ly49 and CD94/NKG2, whereas fetal and neonatal NK cells express only CD94/NKG2. After birth, Ly49+ NK cells slowly increase and CD94/NKG2+ NK cells decrease. The aim of this study was to determine whether murine NK cells develop differently from transplants of fetal liver and adult marrow stem cells and whether the adult marrow microenvironment is critical for NK receptor maturation.: Materials and methodsEnriched populations of stem cells were transplanted into adult mice, and the kinetics of NK receptor acquisition was examined. NK cells from osteopetrotic Csf1op/Csf1op mice, in which hematopoiesis within the marrow is severely limited, were also analyzed.: ResultsNK cells regenerated from both fetal and adult stem cells initially resembled neonatal NK cells in their slow acquisition of Ly49 over several weeks, although the adult stem cell–derived NK cells matured approximately 10 days sooner. NK cells from adult Csf1op/Csf1op mice expressed normal levels of Ly49.: ConclusionMaturation of the NK receptor repertoire is a slow process regardless of their stem cell origin or reduced marrow space caused by osteopetrosis. [Copyright &y& Elsevier]