Invariant natural killer T cells recognize glycolipids from pathogenic Gram-positive bacteria
La Jolla Institute for Allergy and Immunology1, University of Birmingham2, Aaron Diamond AIDS Research Center3, Scripps Research Institute4, National Institutes of Health5, University of British Columbia6, University of Montana7, Kanto Gakuin University8, University of Leicester9, Tohoku University10
TL;DR: The results show how microbial lipids position the sugar for recognition by the invariant TCR and extend the range of microbes recognized by this conserved TCR to several clinically important bacteria.
Abstract: Natural killer T cells (NKT cells) recognize glycolipid antigens presented by CD1d. These cells express an evolutionarily conserved, invariant T cell antigen receptor (TCR), but the forces that drive TCR conservation have remained uncertain. Here we show that NKT cells recognized diacylglycerol-containing glycolipids from Streptococcus pneumoniae, the leading cause of community-acquired pneumonia, and group B Streptococcus, which causes neonatal sepsis and meningitis. Furthermore, CD1d-dependent responses by NKT cells were required for activation and host protection. The glycolipid response was dependent on vaccenic acid, which is present in low concentrations in mammalian cells. Our results show how microbial lipids position the sugar for recognition by the invariant TCR and, most notably, extend the range of microbes recognized by this conserved TCR to several clinically important bacteria.
Citations
More filters
TL;DR: Recent advances in understanding of the innate-like mechanisms underlying iNKT cell activation are discussed and how lipid antigens, the inflammatory milieu and interactions with other immune cell subsets regulate the functions of iN KT cells in health and disease are described.
Abstract: Invariant natural killer T (iNKT) cells exist in a 'poised effector' state, which enables them to rapidly produce cytokines following activation. Using a nearly monospecific T cell receptor, they recognize self and foreign lipid antigens presented by CD1d in a conserved manner, but their activation can catalyse a spectrum of polarized immune responses. In this Review, we discuss recent advances in our understanding of the innate-like mechanisms underlying iNKT cell activation and describe how lipid antigens, the inflammatory milieu and interactions with other immune cell subsets regulate the functions of iNKT cells in health and disease.
686 citations
TL;DR: This Review focuses on the defining features and emerging generalities regarding how NKT cells specifically recognize self, microbial and synthetic lipid-based antigens that are presented by CD1d.
Abstract: Natural killer T (NKT) cells are innate-like T cells that rapidly produce a variety of cytokines following T cell receptor (TCR) activation and can shape the immune response in many different settings. There are two main NKT cell subsets: type I NKT cells are typically characterized by the expression of a semi-invariant TCR, whereas the TCRs expressed by type II NKT cells are more diverse. This Review focuses on the defining features and emerging generalities regarding how NKT cells specifically recognize self, microbial and synthetic lipid-based antigens that are presented by CD1d. Such information is vitally important to better understand, and fully harness, the therapeutic potential of NKT cells.
384 citations
TL;DR: The hallmarks of tissue-resident innate, innate-like, and adaptive lymphocytes, as well as their potential functions in non-lymphoid organs, are discussed.
299 citations
Cites background from "Invariant natural killer T cells re..."
...Functionally, iNKT cells can be activated by potent bacterial ligands, such as cell wall sphingolipids from Sphingomonas, Borrelia, or Streptococcus (Kinjo et al., 2006, 2011; Sriram et al., 2005)....
[...]
TL;DR: Analysis of MAIT cells resident in the vascular bed of livers showed that they represented the majority of T cells expressing NK markers and the dominant IL-17A+ T cell subset in the human liver sinusoids, and it was shown that IL-7, a cytokine produced by hepatocytes during inflammation, regulated TCR-mediated activation ofMAIT cells, licensing them to dramatically increase Th1 cytokines and IL- 17A production.
Abstract: Human mucosal-associated invariant T (MAIT) cells are a T cell population characterized by the expression of a semi-invariant TCR capable of recognizing bacterial products in the context of MR1. MAIT cells are enriched in the human liver, which is constantly exposed to bacterial products from the intestine. Whether this specific parenchymal localization influences their function remains unknown. We analyzed MAIT cells resident in the vascular bed of livers and showed that they represented the majority of T cells expressing NK markers and the dominant IL-17A(+) T cell subset in the human liver sinusoids. In comparison with MAIT cells purified from peripheral blood, intrasinusoidal MAIT cells expressed markers of T cell activation; however, TCR-mediated cytokine production was equally suppressed in both circulating and intrasinusoidal MAIT cells. MAIT cells also expressed high levels of IL-7R, and we showed that IL-7, a cytokine produced by hepatocytes during inflammation, regulated TCR-mediated activation of MAIT cells, licensing them to dramatically increase Th1 cytokines and IL-17A production. Our quantitative and functional data indicate that MAIT cells are a specialized cell population highly adapted to exert their immune functions in the vascular network of the liver.
297 citations
TL;DR: It is shown that purified polyclonal MAIT cells potently inhibit intracellular bacterial growth of Mycobacterium bovis BCG in macrophages in coculture assays, and this inhibitory activity was dependent upon MAIT cell selection by MR1, secretion of gamma interferon (IFN-γ), and an innate interleukin 12 (IL-12) signal from infected MΦ.
Abstract: Mucosa-associated invariant T (MAIT) cells are a unique population of αβ T cells in mammals that reside preferentially in mucosal tissues and express an invariant Vα paired with limited Vβ T-cell receptor (TCR) chains. Furthermore, MAIT cell development is dependent upon the expression of the evolutionarily conserved major histocompatibility complex (MHC) class Ib molecule MR1. Using in vitro assays, recent studies have shown that mouse and human MAIT cells are activated by antigen-presenting cells (APCs) infected with diverse microbes, including numerous bacterial strains and yeasts, but not viral pathogens. However, whether MAIT cells play an important, and perhaps unique, role in controlling microbial infection has remained unclear. To probe MAIT cell function, we show here that purified polyclonal MAIT cells potently inhibit intracellular bacterial growth of Mycobacterium bovis BCG in macrophages (MΦ) in coculture assays, and this inhibitory activity was dependent upon MAIT cell selection by MR1, secretion of gamma interferon (IFN-γ), and an innate interleukin 12 (IL-12) signal from infected MΦ. Surprisingly, however, the cognate recognition of MR1 by MAIT cells on the infected MΦ was found to play only a minor role in MAIT cell effector function. We also report that MAIT cell-deficient mice had higher bacterial loads at early times after infection compared to wild-type (WT) mice, demonstrating that MAIT cells play a unique role among innate lymphocytes in protective immunity against bacterial infection.
249 citations
References
More filters
Journal Article•
TL;DR: Although universal screening for GBS colonization is anticipated to result in further reductions in the burden of GBS disease, the need to monitor for potential adverse consequences of intrapartum antibiotic use, such as emergence of bacterial antimicrobial resistance or increased incidence or severity of non-GBS neonatal pathogens, continues.
Abstract: Despite substantial progress in prevention of perinatal group B streptococcal (GBS) disease since the 1990s, GBS remains the leading cause of early-onset neonatal sepsis in the United States In 1996, CDC, in collaboration with relevant professional societies, published guidelines for the prevention of perinatal group B streptococcal disease (CDC Prevention of perinatal group B streptococcal disease: a public health perspective MMWR 1996;45[No RR-7]); those guidelines were updated and republished in 2002 (CDC Prevention of perinatal group B streptococcal disease: revised guidelines from CDC MMWR 2002;51[No RR-11]) In June 2009, a meeting of clinical and public health representatives was held to reevaluate prevention strategies on the basis of data collected after the issuance of the 2002 guidelines This report presents CDC's updated guidelines, which have been endorsed by the American College of Obstetricians and Gynecologists, the American Academy of Pediatrics, the American College of Nurse-Midwives, the American Academy of Family Physicians, and the American Society for Microbiology The recommendations were made on the basis of available evidence when such evidence was sufficient and on expert opinion when available evidence was insufficient The key changes in the 2010 guidelines include the following: • expanded recommendations on laboratory methods for the identification of GBS, • clarification of the colony-count threshold required for reporting GBS detected in the urine of pregnant women, • updated algorithms for GBS screening and intrapartum chemoprophylaxis for women with preterm labor or preterm premature rupture of membranes, • a change in the recommended dose of penicillin-G for chemoprophylaxis, • updated prophylaxis regimens for women with penicillin allergy, and • a revised algorithm for management of newborns with respect to risk for early-onset GBS disease Universal screening at 35-37 weeks' gestation for maternal GBS colonization and use of intrapartum antibiotic prophylaxis has resulted in substantial reductions in the burden of early-onset GBS disease among newborns Although early-onset GBS disease has become relatively uncommon in recent years, the rates of maternal GBS colonization (and therefore the risk for early-onset GBS disease in the absence of intrapartum antibiotic prophylaxis) remain unchanged since the 1970s Continued efforts are needed to sustain and improve on the progress achieved in the prevention of GBS disease There also is a need to monitor for potential adverse consequences of intrapartum antibiotic prophylaxis (eg, emergence of bacterial antimicrobial resistance or increased incidence or severity of non-GBS neonatal pathogens) In the absence of a licensed GBS vaccine, universal screening and intrapartum antibiotic prophylaxis continue to be the cornerstones of early-onset GBS disease prevention
2,823 citations
"Invariant natural killer T cells re..." refers background in this paper
..., and group B Streptococcus , the leading cause of life-threatening bacterial infections such as sepsis and meningitis in newborn human...
[...]
TL;DR: Characterization of the nonclonal receptors of the innate immune system responsible for the adjuvant activity, and, evidently, for the associated side effects, would provide a powerful alternative approach, which would ultimately allow one to target these receptors directly.
2,452 citations
TL;DR: Glycosylceramide-mediated proliferative responses of Valpha14 NKT cells were abrogated by treatment with chloroquine-concanamycin A or by monoclonal antibodies against CD1d/Vbeta8, CD40/CD40L, or B7/CTLA-4/CD28, but not by interference with the function of a transporter-associated protein.
Abstract: Natural killer T (NKT) lymphocytes express an invariant T cell antigen receptor (TCR) encoded by the Valpha14 and Jalpha281 gene segments. A glycosylceramide-containing alpha-anomeric sugar with a longer fatty acyl chain (C26) and sphingosine base (C18) was identified as a ligand for this TCR. Glycosylceramide-mediated proliferative responses of Valpha14 NKT cells were abrogated by treatment with chloroquine-concanamycin A or by monoclonal antibodies against CD1d/Vbeta8, CD40/CD40L, or B7/CTLA-4/CD28, but not by interference with the function of a transporter-associated protein. Thus, this lymphocyte shares distinct recognition systems with either T or NK cells.
2,411 citations
TL;DR: The need to reinforce current control strategies, develop new primary prevention strategies, and collect better data from developing countries for most diseases is highlighted, as GAS is an important cause of morbidity and mortality.
Abstract: The global burden of disease caused by group A streptococcus (GAS) is not known. We review recent population-based data to estimate the burden of GAS diseases and highlight deficiencies in the available data. We estimate that there are at least 517,000 deaths each year due to severe GAS diseases (eg, acute rheumatic fever, rheumatic heart disease, post-streptococcal glomerulonephritis, and invasive infections). The prevalence of severe GAS disease is at least 18.1 million cases, with 1.78 million new cases each year. The greatest burden is due to rheumatic heart disease, with a prevalence of at least 15.6 million cases, with 282,000 new cases and 233,000 deaths each year. The burden of invasive GAS diseases is unexpectedly high, with at least 663,000 new cases and 163,000 deaths each year. In addition, there are more than 111 million prevalent cases of GAS pyoderma, and over 616 million incident cases per year of GAS pharyngitis. Epidemiological data from developing countries for most diseases is poor. On a global scale, GAS is an important cause of morbidity and mortality. These data emphasise the need to reinforce current control strategies, develop new primary prevention strategies, and collect better data from developing countries.
2,271 citations
TL;DR: The burden of pneumococcal pneumonia is measured by applying the proportion of pneumonia cases caused by S pneumoniae derived from efficacy estimates from vaccine trials to WHO country-specific estimates of all-cause pneumonia cases and deaths, using disease incidence and case-fatality data from a systematic literature review.
2,192 citations