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The high expression of CD1a on Langerhans cells in normal human skin suggests a central role for this lipid antigen presenting molecule in skin homeostasis and immunity. Although the lipid antigen presenting function of CD1a has been known for years, the physiological and pathological functions of the CD1a system in human skin remain incompletely understood. This review provides an overview of this active area of investigation, and discusses recent insights into the functions of CD1a, CD1a-restricted T cells, and lipid antigens in inflammatory and allergic skin disease. We include recent publications and work presented at the biennial CD1-MR1 EMBO workshop held in 2019 in Oxford, regarding lipids that increase and those that decrease T cell responses to CD1a.

Cluster of differentiation 1 (CD1) molecules are Major Histocompatibility Complex (MHC) class I-like proteins that present diverse lipid antigens to T cells instead of peptides. This thesis centers around the question what the biological function of the CD1 isoforms CD1b and CD1c is in T cell immunity. Part I of this thesis explores how CD1b and CD1c present lipid antigens from Mycobacterium tuberculosis to antibacterial T cells. Chapter 2 describes the total synthesis of three mycobacterial diacyltrehalose (DAT) lipids. The small differences in the chemical structure of the lipidic parts of DAT1, DAT2, and DAT3 led to drastic differences in binding by the innate immune receptor Mincle, which could only be activated by DAT3. In chapter 3 we investigated the recognition of mycobacterial DAT lipids by human T cell receptors. Whereas the Mincle receptor only recognizes DAT3, T cells follow a different pattern as observed by binding of DAT1- and DAT2- treated CD1b tetramers, but not DAT3- treated CD1b tetramers. Chapter 4 describes the immunological recognition of three different synthetic mycobacterial mannosyl phosphomycoketide (MPM) analogs designed to withstand hydrolysis to phosphomycoketide. One analog, MPM-3, was hydrolysis-resistant and recognized by human T cells that are cross-reactive to natural MPM. Part II of this thesis describes research on lipid antigen-independent recognition of CD1, also known as CD1 autoreactivity. CD1-mediated T cell autoreactivity has been shown previously, but it is unclear whether that represented a rare event revealed by the methods used in the past, or whether autoreactivity is common in the CD1 system. In chapters 5 and 6 tetramers were used to study CD1 autoreactivity patterns of T cells. Chapter 5 describes the discovery that CD1b is recognized by several human Vd1 gamma delta T cell receptors and stimulates autoreactive responses. The different gamma delta T cell receptors interacted with different surfaces of CD1b and showed different requirements for lipid antigens and co-recognition of butryophilin-like proteins. In chapter 6 we investigated the recognition of CD1c itself by human T cells. Tetramer binding and autoreactivity occurred with CD1c in complex with numerous, chemically diverse self-lipids that were fully seated within the antigen binding cleft, suggesting that the small lipid size is a determinant of autoreactive T cell responses via CD1c. In conclusion, this thesis focuses on recognition of the antigen presenting molecules CD1b and CD1c by the human immune system. Two types of T cell-CD1 interaction are covered here: 1) recognition of CD1 presented mycobacterial lipids by human T cells and 2) the recognition of the CD1 itself, independent of the lipid presented.

SummaryNatural killer T (NKT) cells are an abundant subset of liver lymphocytes activated by lipid antigens presented on CD1d molecules that are expressed by cholangiocytes. We aimed to determine if bile from patients with chronic liver diseases contains antigenic lipids that can activate NKT cells. Using murine invariant (24.7, 24.8 and DN32.D3) and non-invariant (14S.6, 14S.7 and 14S.10) NKT hybridomas we investigated the presence of lipid antigens in bile collected from the gallbladder of patients undergoing liver transplantation due to end-stage liver disease. Biliary microbiota profiles were generated using 16S rRNA amplicon sequencing. We found that the patient bile samples contain antigens that activate both invariant and non-invariant NKT hybridomas (24.7, 24.8, DN32.D3, 14S.6, 14S.7 and 14S.10), as demonstrated by activation of at least one hybridoma by eight of 10 bile samples. Activation at high dilutions suggests that some antigens are highly potent. We used the non-invariant NKT hybridoma 14S.6 to screen 21 additional patient bile samples for NKT-reactivity and demonstrated that 12 of 21 bile samples resulted in activation, three of which gave a strong activation. Four of 12 activating bile samples contained microbial DNA. Our results reveal an immunological pathway that could be of critical importance in biliary immunology.

Natural killer T (NKT) cells are an innate-like T cell subset that recognize lipid antigens presented by CD1d-expressing antigen presenting cells (APCs), such as dendritic cells, macrophages, and B cells. They can be subdivided into two different subsets according to the variation in αβ TCR chains: type I and type II NKT cells. Type I, also called invariant NKT cells (iNKT), express restricted TCRs with an invariant α-chain (Vα24-Jα18 in humans and Vα14-Jα18 in mice) and limited β-chains. Here we have established a protocol in which iNKT cells are isolated from a donor wild-type mouse and transferred into iNKT KO (Jα18-/-) mouse. Below we will explore the methods for cell sorting of splenic iNKTs, iNKT cells transfer, and detection of transferred cells into the liver using flow cytometry technique.

Invariant natural killer T (iNKT) cell is a type of innate-like T cell subsets with both T and NK cell phenotype and functions. They recognize lipid antigens presented by CD1d molecules and can be specifically activated by alpha-galactosylceramide (α-GalCer) in vitro. After activation, iNKT cells expand efficiently and exert direct killing effects. Based on it, we mainly introduce the protocols of detection of human iNKT cell functions in vitro, including in vitro expansion and their cytotoxicity to tumor cells.

Diseases due to mycobacteria, including tuberculosis, leprosy, and Buruli ulcer, rank among the top causes of death and disability worldwide. Animal studies have revealed the importance of T cells in controlling these infections. However, the specific antigens recognized by T cells that confer protective immunity and their associated functions remain to be definitively established. T cells that respond to mycobacterial peptide antigens exhibit classical features of adaptive immunity and have been well-studied in humans and animal models. Recently, innate-like T cells that recognize lipid and metabolite antigens have also been implicated. Specifically, T cells that recognize mycobacterial glycolipid antigens (mycolipids) have been shown to confer protection to tuberculosis in animal models and share some biological characteristics with adaptive and innate-like T cells. Here, we review the existing data suggesting that mycolipid-specific T cells exist on a spectrum of "innateness," which will influence how they can be leveraged to develop new diagnostics and vaccines for mycobacterial diseases.

Tissue homeostasis is critically dependent on the function of tissue-resident lymphocytes, including lipid-reactive invariant natural killer T (iNKT) cells. Yet, if and how the tissue environment shapes the antigen specificity of iNKT cells remains unknown. By analysing iNKT cells from lymphoid tissues of mice and humans we demonstrate that their T cell receptor (TCR) repertoire is highly diverse and is distinct for cells from various tissues resulting in differential lipid-antigen recognition. Within peripheral tissues iNKT cell recent thymic emigrants exhibit a different TCR repertoire than mature cells, suggesting that the iNKT population is shaped after arrival to the periphery. Consistent with this, iNKT cells from different organs show distinct basal activation, proliferation and clonal expansion. Moreover, the iNKT cell TCR repertoire changes following immunisation and is shaped by age and environmental changes. Thus, post-thymic modification of the TCR-repertoire underpins the distinct antigen specificity for iNKT cells in peripheral tissues

Invariant NKT (iNKT) cells have been shown to help B cells in a cognate or noncognate manner; however, whether cognate iNKT cell help induces B cell memory responses remains controversial, and the underlying mechanisms are still unclear. In this study, we demonstrated that, in the absence of follicular helper T cells, cognate iNKT cell help could promote B cell memory responses in mice that were dependent on the formation of memory follicular helper iNKT (iNKTFH) cells and their interactions with memory B cells in recall responses. Generation of memory iNKTFH cells required lipid Ag presentation by dendritic cells but not by B cells. Upon rechallenge, memory iNKTFH cells recognized lipid Ags presented by memory B cells, which recalled iNKTFH effector cells and elicited B cell memory responses. However, LPS, which promoted the synthesis of self-lipids, failed to elicit recall responses in the absence of exogenous lipid Ags.

IMPACT: Examining lipid immunity for Mycobacterium tuberculosis in a translatable Guinea pig model may serve as a critical foundation for the creation of an efficacious human lipid based vaccine against tuberculosis. OBJECTIVES/GOALS: CD1 is a group of glycoproteins on antigen-presenting cells (APCs) that present lipid antigens to T cells. Mycobacterium tuberculosis (Mtb) has a lipid-rich cell wall which is essential for the pathogenesis of tuberculosis. Our goal is to determine the frequency, phenotypes, and functionality of CD1 T cells against Mtb using the guinea pig model. METHODS/STUDY POPULATION: Guinea pigs serve as the best translational model for CD1 immunology as they have both group 1 and group 2 CD1 complexes, comparable to human CD1. We performed ex-vivo and in-vivo experiments to analyze lipid antigen-specific CD1 T cell responses with Mtb infection. Assays to detect lipid-specific CD1 T cell activation include cellular proliferation, cytotoxicity assays, and interferon-gamma (IFNγ) release assay (Elispot) using both synthetic and Mtb-derived lipids. We isolated and characterized CD1 T cells using tetramerized CD1 complexes loaded with specific Mtb lipids. Spatial interaction between lipid loaded CD1 APCs with CD1 T cells were demonstrated by immunohistochemistry (IHC). Lastly, we will investigate the impact of lipid-based immunology via knockdown and overexpression of CD1 complexes. RESULTS/ANTICIPATED RESULTS: The cytotoxicity assay demonstrated that the CD1b1 and CD1b3 complexes play roles in the presentation of Mtb lipids, specifically glucose monomycolate, and mycolic acid, as noted by T cell killing of fibroblasts that express specific CD1 complexes that can present Mtb lipids. Similarly, cellular proliferation exhibited lipid specific T cell proliferation. IFNγ production by the stimulated CD1-restricted T cells (Elispot) was weak indicating CD1 T cells may not produce IFNγ. IHC successfully showed CD1 APCs in lungs and spleens of infected guinea pigs. It is anticipated that knocking out CD1 expression will lead to impaired immunity, and increase severity of disease as noted by pathologic lesions/bacterial burden, and systemic spread; in contrast, CD1 enhancement will limit the severity of tuberculosis. DISCUSSION/SIGNIFICANCE OF FINDINGS: We characterized CD1 T cells in infected guinea pigs at the tissue level, demonstrating Mtb lipid immunology. As a result, we laid the groundwork for investigating whether augmenting lipid immunity in the guinea pig model will enhance immunity against tuberculosis. Fruition of such work may lead to the development of effective tuberculosis vaccines.

Glioblastoma is an aggressive and deadly cancer, but to date, immunotherapies have failed to make significant strides in improving prognoses for glioblastoma patients. One of the current challenges to developing immunological interventions for glioblastoma is our incomplete understanding of the numerous immunoregulatory mechanisms at play in the glioblastoma tumor microenvironment. We propose that Natural Killer T (NKT) cells, which are unconventional T lymphocytes that recognize lipid antigens presented by CD1d molecules, may play a key immunoregulatory role in glioblastoma. For example, evidence suggests that the activation of type I NKT cells can facilitate anti-glioblastoma immune responses. On the other hand, type II NKT cells are known to play an immunosuppressive role in other cancers, as well as to cross-regulate type I NKT cell activity, although their specific role in glioblastoma remains largely unclear. This review provides a summary of our current understanding of NKT cells in the immunoregulation of glioblastoma as well as highlights the involvement of NKT cells in other cancers and central nervous system diseases.

Background: Natural Killer T (NKT) cells are CD1d-restricted innate-like T cells that can rapidly release stored cytokines upon recognition of lipid antigens. In mice, type I NKT cells seem to promote liver inflammation, whereas type II NKT cells seem to restrict hepatitis. Here, we aimed at characterizing the role of human type I and type II NKT in patients with autoimmune hepatitis (AIH).Methods: NKT cells were analyzed by flow cytometry in peripheral blood and liver of AIH patients and control groups. α-galactosylceramide-loaded or sulfatide-loaded tetramers were used to detect type I or II NKT cells, respectively. Hepatic CD1d was stained by in situ-hybridization of liver biopsies.Results and Conclusions: Type II NKT cells were more prevalent in human peripheral blood and liver than type I NKT cells. In AIH patients, the frequency of sulfatide-reactive type II NKT cells was significantly increased in peripheral blood (0.11% of peripheral blood leukocytes) and liver (3.78% of intrahepatic leukocytes) compared to healthy individuals (0.05% and 1.82%) and patients with drug-induced liver injury (0.06% and 2.03%; p < 0.05). Intrahepatic type II NKT cells of AIH patients had a different cytokine profile than healthy subjects with an increased frequency of TNFα (77.8% vs. 59.1%, p < 0.05), decreased IFNγ (32.7% vs. 63.0%, p < 0.05) and a complete lack of IL-4 expressing cells (0% vs. 2.1%, p < 0.05). T cells in portal tracts expressed significantly more CD1d-RNA in AIH livers compared to controls. This study supports that in contrast to their assumed protective role in mice, human intrahepatic, sulfatide-reactive type II NKT cells displayed a proinflammatory cytokine profile in patients with AIH. Infiltrating T cells in portal areas of AIH patients overexpressed CD1d and could thereby activate type II NKT cells.

Lyme disease is a common multi-system disease caused by infection with a tick-transmitted spirochete, Borrelia burgdorferi and related Borrelia species. The monoglycosylated diacylglycerol known as B. burgdorferi glycolipid II (BbGL-II) is a major target of antibodies in sera from infected individuals. Here we show that CD1b presents BbGL-II to human T cells and that the T cell receptor (TCR) mediates the recognition. However, we did not detect increased frequency of CD1b-BbGL-II binding T cells in the peripheral blood of Lyme disease patients compared to controls. Unexpectedly, mapping the T cell specificity for BbGL-II-like molecules using tetramers and activation assays revealed a concomitant response to CD1b-expressing antigen presenting cells in absence of BbGL-II. Further, among all major classes of self-lipid tested, BbGL-II responsive TCRs show strong cross-reactivity to diacylglycerol, a self-lipid antigen with structural similarities to BbGL-II. Extending prior work on MHC and CD1b, CD1c, and CD1d proteins, this study provides evidence for cross-reactive CD1b-restricted T cell responses to bacterial and self-antigens, and identifies chemically defined targets for future discovery of self and foreign antigen cross-reactive T cells. This article is protected by copyright. All rights reserved.

The synthesis of single mono-arabino mycolates, important lipid antigens from mycobacteria is described, using structurally defined synthetic mycolic acids. Preliminary assays indicate that these are differentially antigenic to antibodies in the serum of people with active tuberculosis.

Paratuberculosis (PTB) or Johne’s disease is a common ruminant infectious disease caused by Mycobacterium avium subsp. paratuberculosis (MAP). In this study, two MAP antigens were compared for their diagnostic utility to detect subclinical PTB in a sheep flock in Mexicali, Mexico. Sheep (n = 31) without clinical signs but positive on a direct fecal-polymerase chain reaction were tested with two preabsorbed in-house enzyme linked immunosorbent assays (ELISAs) using: (1) an ethanol-extracted surface lipid antigen (EVELISA) and (2) a protoplasmic antigen (ELISA-PPA). Sensitivities of the EVELISA and ELISA-PPA were 84% (95% CI; 66–95%) and 29% (95% CI; 14–48%), respectively. The EVELISA test could be a fast and effective way to identify subclinical ovine PTB for severely affected flocks.

CD1d-restricted invariant NKT (iNKT) cells are a group of innate-like regulatory T cells that recognize lipid antigens. Both mouse modeling experiments and human clinical studies have suggested a key role for iNKT cells in anti-HBV immunity and these potent T cells can be explored as a novel therapeutic target for anti-HBV treatment. We aim to humanize mice in the CD1d/iNKT cell lipid presentation system and provide new research tools for identifying novel anti-HBV agents.

Atherosclerosis and its derived cardiovascular diseases are a leading cause of death in the western world. The treatment of atherosclerosis is currently based on lipid lowering in combination with anti-inflammatory therapies that slow the progression of atherosclerosis. Still, these therapies are not able to fully inhibit the formation or progression of atherosclerotic lesions. Ever since it was first demonstrated that the immunological system plays an important role during atherogenesis, various different immunotherapeutic approaches have been evaluated with promising results. Notwithstanding that, one of the difficulties in developing effective vaccination strategies for atherosclerosis is the selection of a specific target. So far, vaccination strategies have been based on the targeting of lipid antigens, inflammation-derived antigens, and cell-based vaccination strategies. More recently, strategies aimed at blocking the retention of low-density lipoproteins by arterial proteoglycans have emerged as a promising tool. In the study at hand we reviewed the most relevant advances on atherosclerosis immunotherapy cited in the PubMed database from 1980 to 2012.

SUMMARY Lipid antigens of Leishmania donovani like lipophosphoglycans are shown as a potent ligand for the activation of invariant natural killer T (iNKT) cells. It is reported that activation of iNKT cells augments the disease pathology in experimental visceral leishmaniasis (VL). In this study, we demonstrate the enrichment of iNKT cells in the bone marrow, one of the disease sites among patients with VL.

Invariant natural killer T (iNKT) cells recognize endogenous and exogenous lipids in the context of CD1d molecules, and through the activation and maturation of dendritic cells and B cells, can significantly enhance priming of antigen-specific T and B cell responses. Recent findings have provided important insights into the recognition of several novel endogenous lipids by iNKT cells, and into the mechanisms controlling their generation and loading onto CD1d molecules. In this review we discuss these latest findings and describe the role of autophagy in iNKT cell development and activation.

Self-glycosphingolipids bind to surface CD1 molecules and are readily displaced by other CD1 ligands. This capacity to exchange antigens at the cell surface is not common to other antigen-presenting molecules and its physiological importance is unclear. Here we show that a large pool of cell-surface CD1a, but not CD1b molecules, is stabilized by exogenous lipids present in serum. Under serum deprivation CD1a molecules are altered and functionally inactive, as they are unable to present lipid antigens to T cells. Glycosphingolipids and phospholipids bind to, and restore functionality to CD1a without the contribution of newly synthesized and recycling CD1a molecules. The dependence of CD1a stability on exogenous lipids is not related to its intracellular traffic and rather to its antigen-binding pockets. These results indicate a functional dichotomy between CD1a and CD1b molecules and provide new information on how the lipid antigenic repertoire is immunologically sampled.

Natural killer T (NKT) cells are a unique immunoregulatory T cell population that is positively selected by CD1d-expressing thymocytes. Previous studies have shown that NKT cells exhibit autoreactivity, which raises the question of whether they are subject to negative selection. Here, we report that the addition of agonist glycolipid α-galactosylceramide (α-GalCer) to a fetal thymic organ culture (FTOC) induces a dose-dependent disappearance of NKT cells, suggesting that NKT cells are susceptible to negative selection. Overexpression of CD1d in transgenic (Tg) mice results in reduced numbers of NKT cells, and the residual NKT cells in CD1d-Tg mice exhibit both an altered Vβ usage and a reduced sensitivity to antigen. Furthermore, bone marrow (BM) chimeras between Tg and WT mice reveal that CD1d-expressing BM-derived dendritic cells, but not thymic epithelial cells, mediate the efficient negative selection of NKT cells. Thus, our data suggest that NKT cells developmentally undergo negative selection when engaged by high-avidity antigen or abundant self-antigen.

The microbiota control regional immunity using mechanisms such as inducing IL-17A-producing γδ T (γδT-17) cells in various tissues. However, little is known regarding hepatic γδT cells that are constantly stimulated by gut commensal microbes. Here we show hepatic γδT cells are liver-resident cells and predominant producers of IL-17A. The microbiota sustain hepatic γδT-17 cell homeostasis, including activation, survival and proliferation. The global commensal quantity affects the number of liver-resident γδT-17 cells; indeed, E. coli alone can generate γδT-17 cells in a dose-dependent manner. Liver-resident γδT-17 cell homeostasis depends on hepatocyte-expressed CD1d, that present lipid antigen, but not Toll-like receptors or IL-1/IL-23 receptor signalling. Supplementing mice in vivo or loading hepatocytes in vitro with exogenous commensal lipid antigens augments the hepatic γδT-17 cell number. Moreover, the microbiota accelerate nonalcoholic fatty liver disease through hepatic γδT-17 cells. Thus, our work describes a unique liver-resident γδT-17 cell subset maintained by gut commensal microbes through CD1d/lipid antigens., γδ T cells are major producers of IL-17A in response to microbial infection. Here the authors show that a high load of commensal microbes can maintain homeostasis of IL-17A+ γδ T cells in the liver via CD1d antigen presentation, with implications for liver diseases.

Several autoantibodies related to Type 1 diabetes mellitus and their corresponding autoantigens have been previously identified. While peptide antigens are more widely recognized, lipid antigens like sulfatides and gangliosides are also known epitopes for the diabetic humoral immune response. Islet cell antibodies (ICA) in Type 1 diabetes are heterogeneous immunoglobulins directed against selected antigens in the islets of Langerhans. Moreover, ICA may be the best predictive marker of disease in family members of patients with Type 1 diabetes. The aims of this study were: (1) to purify lipids from porcine pancreas that contain ICA epitopes; (2) to characterize these lipid antigens, and (3) to use the purified lipids in an assay to detect antibodies in patients with Type 1 diabetes. A unique family of 4 lysophospholipids, 1 fully characterized as lysophosphatidylmyoinositol, partially inhibited ICA staining, and therefore, were considered to be candidate antigens for an ICA immunoassay. Using a dot blot immunoassay, we detected antibodies directed against these phospholipids in 28 out of 46 (61%) diabetic sera, while detecting only 1 false positive out of 28 nondiabetic sera (3.6%; p < 0.0001 comparing diabetic vs. nondiabetic serum). Therefore, lysophospholipid immunoassay positivity is present in sera of Type 1 diabetic patients. Furthermore, we detected 15 out of 23 ICA-negative diabetic sera (65.2%), showing that our phospholipid immunoassay does not correlate with ICA positivity.

Immunologists continue to unveil a startling diversity in the antigenic repertoire of T cells, which now rivals that of B cells. In his Perspective, De Libero discusses new work ( Zhou et al., Moody et al.) that adds lipopeptide antigens to the list of T cell immunogens and reveals how lipid antigens are handled in antigen-presenting cells and then presented to T cells.

A family of neutral glycosphingolipids containing a 3-O-acetyl-sphingosine galactosylceramide (3-SAG) has been characterized. Seven new derivatives of galactosylceramide (GalCer), designated as fast-migrating cerebrosides (FMCs) by TLC retention factor, have been identified. The simplest compounds – FMC-1 and FMC-2 – of this series have been characterized as the 3-SAG containing nonhydroxy and hydroxy fatty acyl, respectively. The next two – FMC-3 and FMC-4 – add 6-O-acetyl-galactose and the most complex glycosphingolipids, FMC-5, -6 and -7, are 2,3,4,6-tetra-O-acetyl-3-SAG. These hydrophobic myelin lipid biomarkers coappear with GalCer during myelinogenesis and disappear along with GalCer in de- or dys-myelinating disorders. Myelin lipid antigens, including FMCs, are keys to myelin biology, opening the possibility of new and novel immune modulatory tools for treatment of autoimmune diseases including multiple sclerosis.

Bine, S Haziot, A Malikova, I Pelletier, J Charron, D Boucraut, J Mooney, N Gelin, C Research Support, Non-U.S. Gov't England Clinical and experimental immunology Clin Exp Immunol. 2012 Jul;169(1):10-6. doi: 10.1111/j.1365-2249.2012.04586.x.; Studies of multiple sclerosis (MS) have concentrated mainly on antigen presentation of peptides derived from the myelin sheath, while the implication of lipid antigen has been less explored in this pathology. As the extracellular environment regulates expression of the lipid antigen-presenting molecule CD1, we have examined whether sera from patients alters CD1 surface expression in monocyte-derived dendritic cells. We have shown that: (i) CD1 group 1 proteins were highly expressed in the presence of MS sera; (ii) sera from MS patients differentially regulated CD1 group 1 versus CD1 group 2 molecular expression; and (iii) CD1 was expressed strongly in monocytes from MS patients under immunosuppressive treatment. Overall, these results reveal that CD1 expression is modified in MS and provide novel information on the regulation of lipid antigen presentation in myeloid cells.

T cells recognizing lipid antigens are present in large numbers in circulating blood. They exert multiple functions including immunoregulation, tumour surveillance and protection during infection. Here, we review the latest information on the mechanisms of lipid antigen presentation by CD1 molecules. Recent studies have provided insight into CD1 trafficking within the cell, lipid distribution and handling, CD1 maturation, lipid antigen processing and loading. The structural resolution of all human CD1 molecules has revealed unique features that correlate with function. Molecular mechanisms regulating CD1 expression and multiple evasion mechanisms evolved by viral and bacterial pathogens have been disclosed. With rapid progression, these studies have decoded lipid-specific immunity and have revealed the important immunological role of this type of antigen recognition.

Natural killer T cells recognize lipid antigens in the context of CD1 molecules. Recent publications show that this mode of recognition differs substantially from that of classic T-cell receptor peptide-major histocompatibility complex interaction.

Section 1 - Molecular Biology.- Chapter 1 - Evolutionary Biology of the CD1.- Chapter 2 - Architecture of CD1 Proteins.- Chapter 3 - Structures and Biology of Self Lipid Antigens.- Chapter 4 - Structures and Functions of Microbial Lipid Antigens.- Section 2 - Cellular Biology.- Chapter 5 - CD1 Expression on Antigen Presenting Cells.- Chapter 6 - Pathways of CD1 and Lipid Antigen Delivery, Trafficking, Processing, Loading and Presentation.- Chapter 7 - TCR-Mediated Recognition of Glycolipid CD1 Complexes.- Chapter 8 - Development and Selection of Va14i NKT Cells.- Section 3 - Disease.- Chapter 9 - CD1-Restricted T Cells in Host Defense to Infectious Diseases.- Chapter 10 - NKT Cells and Autoimmune Diseases: Unraveling the Complexity.- Chapter 11 - iNKT Cells in Allergic Disease.- Chapter 12 - CD1-Restricted T Cells and Tumor Immunity.- Chapter 13 - Harnessing NKT Cells for Therapeutic Applications.- Subject index

The CD1d-dependent presentation of lipid antigens to natural killer T (NKT) cells is an integral part of the innate immune system. However, the development of anticancer therapies based on NKT-cell agonists has had limited success so far. Humanizing mice with respect to the CD1d/NKT antigen presentation system will provide a tool to identify novel lipids that exert antineoplastic functions by targeting NKT cells before the initiation of costly and lengthy clinical trials.

Background Invariant natural killer T (iNKT) cells are a small subset of T lymphocytes which express a invariant TCR and recognize lipid antigens. They are implicated in a range of immune responses but their role in allergy is controversial. Pollens are the most important trigger of allergic symptoms but their lipid contents may also have a role in allergy through interaction with iNKT cells. The aim of this study was to evaluate the in vitro effect of pollen lipid extract on iNKT cells.

Long-term effects of life-long (>2 year) repeated intravenous injections (up to 17) of high doses of liposomes, lipid A, or liposomes containing lipid A were assessed in BALB/c mice. the liposomes contained dipalmitoylphosphatidylcholine, and cholesterol (1/0.75). When compared with mice injected only with normal saline, there were no statistical differences in life spans observed between the different groups. Animals injected with liposomes or liposomes containing lipid A gradually developed “ruffled” fur, but the animals did not appear sick otherwise, and no differences were observed in the mean weights of the animals in the different groups. All of the animals that were tested in each group, including those injected with normal saline, developed IgG antibodies against one or more of nine lipid antigens. the antibodies were detected by a solid-phase enzyme-linked immunosorbent assay (ELisA) and the antigens consisted of either lipid A or one of eight different phospholipids. After 765 days, when...

In general practice, the following questions often arise in relation to syphilitic and nonsyphilitic serodiagnostic reactions: How is it possible for serum reactions employing lipid antigens apparently unrelated to Treponema pallidum to behave as though they were specifically associated with syphilis, indicated by the remarkable parallelism between serologic and clinical findings in this disease? How can these same serum reactions also behave as though they were totally unrelated to syphilis, as shown by instances of biologically false positive reactions in various nonsyphilitic situations? If a positive serodiagnostic reaction in syphilis indicates the existence of this disease, what is the meaning of a positive reaction in the absence of syphilis? To answer these questions, it will be necessary to examine the relationship between the serodiagnostic reaction and the more comprehensive universal serologic reaction.1 THE UNIVERSAL REACTION Serodiagnostic reactions stem from the universal serologic reaction. The universal reaction is a lipid

This text is presented in four parts. Each part is rather complete within itself. Thus, its appeal will reach those of varied interest in the general subject of the serology of syphilis. This of course leads to some repetition for those who view the book as a whole. Except for the very excellent chapter on the history of the Wassermann and early flocculation tests, this book deals chiefly with the author's experience in the development of the various Kahn test procedures over a period of the last 25 years. In Part I, his new concept of the universal reaction is presented and illustrated with charts, diagrams and tables. He states that some of his previous conclusions were in error and shows that the capacity of serum to react with tissue extract antigen is not limited to syphilis but that non-syphilitic serum possesses this same capacity.The author stresses that there exists a biologically universal tendency for serum, whether human or animal,to give serologic reactions with lipid antigen.

IT PREVIOUSLY has been reported * that the Treponema pallidum immobilization (TPI) test may be nonreactive during the primary and secondary stages of syphilis. The lipid antigen serologic tests for syphilis, e. g., Kahn, Kolmer, VDRL slide, Rein-Bossak, also may be negative in the presence of dark-field-positive lesions of primary syphilis, but are invariably reactive during the secondary stage of syphilis. 4 This study of previously untreated dark-field-positive primary and secondary syphilis patients was undertaken to compare the sensitivity of the TPI test, as modified by Portnoy, Harris, and Olansky, 5 in these stages of syphilis with that of the VDRL slide flocculation quantitative and Rein-Bossak slide flocculation quantitative tests. CLINICAL MATERIAL Thirty patients with dark-field-positive primary syphilis and 20 patients with dark-field-positive secondary syphilis, who had no history of previous treatment for syphilis at any time, were studied. These were patients either of the AtlantaFulton