The pathophysiological functions of proline-glutamic acid (PE)/proline-proline-glutamic acid (PPE) family of proteins of Mycobacterium tuberculosis are not well understood. In this study, we demonstrate that one of the PPE proteins, PPE18 can stimulate macrophages to secrete IL-10, known to favor a Th2 type response. The recombinant PPE18 was found to specifically interact with the TLR2 leading to an early and sustained activation of p38 MAPK, which is critical for IL-10 induction. In silico docking analyses and mutation experiments indicate that PPE18 specifically interacts with the leucine rich repeat 11 approximately 15 domain of TLR2 and the site of interaction is different from that of a synthetic lipopeptide Pam(3)CSK(4) known to activate predominantly ERK 1/2. When PMA-differentiated THP-1 macrophages were infected with a mutant Mycobacterium tuberculosis strain lacking the PPE18, produced poorer levels of IL-10 as compared with those infected with the wild-type strain. In contrast, an M. smegmatis strain overexpressing the PPE18 induced higher levels of IL-10 in infected macrophages. Our data indicate that the PPE18 protein may trigger an anti-inflammatory response by inducing IL-10 production.
Natural killer T (NKT) cells are specialized CD1d-restricted T cells that recognize lipid antigens. Following stimulation, NKT cells lead to downstream activation of both innate and adaptive immune cells in the tumor microenvironment. This has impelled the development of NKT cell-targeted immunotherapies for treating cancer. In this review, we provide a brief overview of the stimulatory and regulatory functions of NKT cells in tumor immunity as well as highlight preclinical and clinical studies based on NKT cells. Finally, we discuss future perspectives to better harness the potential of NKT cells for cancer therapy.
Summary Antigen-driven selection has been implicated in the pathogenesis of monoclonal gammopathies. Patients with Gaucher’s disease have an increased risk of monoclonal gammopathies. Here we show that the clonal immunoglobulin in patients with Gaucher’s disease and in mouse models of Gaucher’s disease–associated gammopathy is reactive against lyso-glucosylceramide (LGL1), which is markedly elevated in these patients and mice. Clonal immunoglobulin in 33% of sporadic human monoclonal gammopathies is also specific for the lysolipids LGL1 and lysophosphatidylcholine (LPC). Substrate reduction ameliorates Gaucher’s disease–associated gammopathy in mice. Thus, longterm immune activation by lysolipids may underlie both Gaucher’s disease–associated gammopathies and some sporadic monoclonal gammopathies.
Key Points• Broad immune activation after a combination of lenalidomide and a-GalCer-loaded dendritic cells.• Proof of principle for harnessing NK T cells to prevent cancer in humans. Natural killer T (iNKT) cells can help IntroductionNatural killer T (NKT) cells are distinct innate CD1d-restricted T cells that recognize lipid antigens. 1 The best-studied subset of NKT cells in both mice and humans are type I NKT cells that express an invariant T-cell receptor. Several studies have described potent antitumor properties of iNKT cells in preclinical models and iNKT cells have also been implicated in immune surveillance against both spontaneous as well as carcinogeninduced murine tumors. 2,3 While iNKT cells can mediate lysis of tumor cells, their antitumor effects likely depend in large part on their ability to activate other immune cells such as NK and dendritic cells (DCs) and recruit adaptive immunity as well as mediate antiangiogenesis. 4-6 ␣-galactosylceramide (␣-GalCer) is a potent prototypic ligand for both human and murine iNKT cells. 7 The availability of clinical-grade ␣-GalCer (KRN7000; KHK) allowed testing of iNKT-targeted approaches in humans. 8 Initial studies with injection of soluble KRN7000 led to only modest effects in humans. [9][10][11] Preclinical studies suggested that targeting ␣-GalCer to DCs led to superior activation of NKT cells in vivo. 12 In a prior study, we have shown that the injection of ␣-GalCer-loaded human DCs led to a clear increase in circulating iNKT cells in vivo. 13 However, these cells were still functionally deficient and, importantly, little activation of downstream innate immune function (including NK cells) was observed.It is now clear that nearly all cases of clinical myeloma (MM) are preceded by an asymptomatic precursor state, including a phase termed as asymptomatic multiple myeloma (AMM). 14 Patients with AMM are currently observed but carry high risk for progression to clinical MM requiring therapy. Strategies to prevent clinical MM may therefore have a major impact on disease-related morbidity and mortality. 14 In prior studies, we have shown that progression from precursor to clinical MM is associated with progressive dysfunction of iNKT cells in vivo. 15 Myeloma is an attractive tumor for NKT-targeted approaches because tumor cells commonly express CD1d and are sensitive to lysis by both NKT as well as NK cells. 15,16 In the past decade, incorporation of immunomodulatory drugs such as lenalidomide (LEN) into clinical care has improved outcome in human MM. 17 An important property of these drugs is providing costimulation of both human T cells as well as NKT cells in culture in an antigen-dependent manner. 18-20 Therefore, we hypothesized that the combination of LEN with ␣-GalCer-loaded DCs will lead to synergistic activation of innate lymphocytes in vivo and mediate antitumor effects in the preventive setting. As LEN alone has some single-agent activity in MM, 21 we chose to test a LEN dose of 10 mg/d, which is lower than the usual starting dose (25 mg/d) in ...
Key Points• A new subset of human and murine type II NKT-T FH cells against Gaucher lipids that regulate B-cell immunity.• A novel pathway for B-cell help providing a mechanism underlying chronic B-cell activation and gammopathy in metabolic lipid disorders.Chronic inflammation including B-cell activation is commonly observed in both inherited (Gaucher disease [GD]) and acquired disorders of lipid metabolism. However, the cellular mechanisms underlying B-cell activation in these settings remain to be elucidated. Here, we report that b-glucosylceramide 22:0 (bGL1-22) and glucosylsphingosine (LGL1), 2 major sphingolipids accumulated in GD, can be recognized by a distinct subset of CD1d-restricted human and murine type II natural killer T (NKT) cells. Human bGL1-22-and LGL1-reactive CD1d tetramer-positive T cells have a distinct T-cell receptor usage and genomic and cytokine profiles compared with the classical type I NKT cells. In contrast to type I NKT cells, bGL1-22-and LGL1-specific NKT cells constitutively express T-follicular helper (T FH ) phenotype. Injection of these lipids leads to an increase in respective lipidspecific type II NKT cells in vivo and downstream induction of germinal center B cells, hypergammaglobulinemia, and production of antilipid antibodies. Human bGL1-22-and LGL1-specific NKT cells can provide efficient cognate help to B cells in vitro. Frequency of LGL1-specific T cells in GD mouse models and patients correlates with disease activity and therapeutic response. Our studies identify a novel type II NKT-mediated pathway for glucosphingolipid-mediated dysregulation of humoral immunity and increased risk of B-cell malignancy observed in metabolic lipid disorders. (Blood. 2015;125(8):1256-1271
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.