Foreign Lipid Research Articles

Insights into the heterogeneity of iNKT cells: tissue-resident and circulating subsets shaped by local microenvironmental cues.

Invariant natural killer T (iNKT) cells are a distinct subpopulation of innate-like T lymphocytes. They are characterized by semi-invariant T cell receptors (TCRs) that recognize both self and foreign lipid antigens presented by CD1d, a non-polymorphic MHC class I-like molecule. iNKT cells play a critical role in stimulating innate and adaptive immune responses, providing an effective defense against infections and cancers, while also contributing to chronic inflammation. The functions of iNKT cells are specific to their location, ranging from lymphoid to non-lymphoid tissues, such as the thymus, lung, liver, intestine, and adipose tissue. This review aims to provide insights into the heterogeneity of development and function in iNKT cells. First, we will review the expression of master transcription factors that define subsets of iNKT cells and their production of effector molecules such as cytokines and granzymes. In this article, we describe the gene expression profiles contributing to the kinetics, distribution, and cytotoxicity of iNKT cells across different tissue types. We also review the impact of cytokine production in distinct immune microenvironments on iNKT cell heterogeneity, highlighting a recently identified circulating iNKT cell subset. Additionally, we explore the potential of exploiting iNKT cell heterogeneity to create potent immunotherapies for human cancers in the future.

CD1a and skin T cells: a pathway for therapeutic intervention.

The CD1 and MR1 protein families present lipid antigens and small molecules to T cells, complementing well-studied major histocompatibility complex-peptide mechanisms. The CD1a subtype is highly and continuously expressed within the skin, most notably on Langerhans cells, and has been demonstrated to present self and foreign lipids to T cells, highlighting its cutaneous sentinel role. Alteration of CD1a-dependent T-cell responses has recently been discovered to contribute to the pathogenesis of several inflammatory skin diseases. In this review, we overview the structure and role of CD1a and outline the current evidence implicating CD1a in the development of psoriasis, atopic dermatitis and allergic contact dermatitis.

Lipoproteins act as vehicles for lipid antigen delivery and activation of invariant natural killer T cells.

Invariant natural killer T (iNKT) cells act at the interface between lipid metabolism and immunity because of their restriction to lipid antigens presented on CD1d by antigen-presenting cells (APCs). How foreign lipid antigens are delivered to APCs remains elusive. Since lipoproteins routinely bind glycosylceramides structurally similar to lipid antigens, we hypothesized that circulating lipoproteins form complexes with foreign lipid antigens. In this study, we used 2-color fluorescence correlation spectroscopy to show, for the first time to our knowledge, stable complex formation of lipid antigens α-galactosylceramide (αGalCer), isoglobotrihexosylceramide, and OCH, a sphingosine-truncated analog of αGalCer, with VLDL and/or LDL in vitro and in vivo. We demonstrate LDL receptor-mediated (LDLR-mediated) uptake of lipoprotein-αGalCer complexes by APCs, leading to potent complex-mediated activation of iNKT cells in vitro and in vivo. Finally, LDLR-mutant PBMCs of patients with familial hypercholesterolemia showed impaired activation and proliferation of iNKT cells upon stimulation, underscoring the relevance of lipoproteins as a lipid antigen delivery system in humans. Taken together, circulating lipoproteins form complexes with lipid antigens to facilitate their transport and uptake by APCs, leading to enhanced iNKT cell activation. This study thereby reveals a potentially novel mechanism of lipid antigen delivery to APCs and provides further insight into the immunological capacities of circulating lipoproteins.

Evaluation of 1,2-diacyl-3-acetyl triacylglycerol production in Yarrowia lipolytica

Plants produce many high-value oleochemical molecules. While oil-crop agriculture is performed at industrial scales, suitable land is not available to meet global oleochemical demand. Worse, establishing new oil-crop farms often comes with the environmental cost of tropical deforestation. The field of metabolic engineering offers tools to transplant oleochemical metabolism into tractable hosts while simultaneously providing access to molecules produced by non-agricultural plants. Here, we evaluate strategies for rewiring metabolism in the oleaginous yeast Yarrowia lipolytica to synthesize a foreign lipid, 3-acetyl-1,2-diacyl-sn-glycerol (acTAG). Oils made up of acTAG have a reduced viscosity and melting point relative to traditional triacylglycerol oils making them attractive as low-grade diesels, lubricants, and emulsifiers. This manuscript describes a metabolic engineering study that established acTAG production at g/L scale, exploration of the impact of lipid bodies on acTAG titer, and a techno-economic analysis that establishes the performance benchmarks required for microbial acTAG production to be economically feasible.

Bispecific Vγ9Vδ2-T and Type 1 NKT Cell Engager Lava-051 As First-in-Class Clinical Candidate to Target CD1d Expressing CLL, MM and AML

Bispecific Vγ9Vδ2-T and Type 1 NKT Cell Engager Lava-051 As First-in-Class Clinical Candidate to Target CD1d Expressing CLL, MM and AML

Abstract 1855: Potent anti-tumor activity against patient CLL, MM and AML by LAVA-051, a bispecific Vγ9Vδ2-T and type 1 NKT cell engager targeting CD1d

Abstract Bispecific antibodies that target tumors by engaging innate-like semi-invariant T cell subsets with inherent anti-tumor activity, such as Vγ9Vδ2-T cells and type 1 natural killer T (NKT) cells, may combine high therapeutic efficacy with limited off-tumor toxicity. Type 1 NKT cells respond to self and foreign (glyco)lipid antigens presented in the context of the MHC class I like molecule CD1d which is expressed on various (hematological) malignancies. Vγ9Vδ2-T cells respond to intracellular accumulation of phosphoantigens in cancer cells by sensing conformational alterations in the butyrophilin (BTN)2A1-3A1 complex. By linking a CD1d-specific single domain antibody (VHH) to a Vδ2-TCR specific VHH, we created a bispecific VHH, termed LAVA-051. Besides targeting Vγ9Vδ2-T cells to CD1d-expressing tumor cells, LAVA-051 has the unique ability to also trigger strong activation of type 1 NKT cells in a CD1d-restricted fashion, resulting in potent killing of CD1d-expressing tumor cells by engagement of Vγ9Vδ2-T cells and/or type 1 NKT cells (EC50 1 pM for Vγ9Vδ2-T cells and 216 pM for type 1 NKT cells; >85% target cell lysis in overnight assays at low effector:target ratios of 1:2). LAVA-051 triggered strong activation, pro-inflammatory cytokine production, and proliferation of type 1 NKT and Vγ9Vδ2-T cells and exerted substantial antitumor activity against human primary acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) cells that express CD1d. Moreover, improved survival was observed in in vivo AML and MM mouse models. Due to lack of cross-reactivity of LAVA-051 with non-human primate (NHP) CD1d and Vγ9Vδ2-T cells, a cross-reactive surrogate bispecific engager was generated to assess safety, pharmacokinetic (PK) and pharmacodynamic (PD) parameters. Multiple dose studies in NHP (7 daily doses up to 1 mg/kg i.v.) showed clear signs of Vγ9Vδ2-T cell engagement but no clinical, laboratory, or histopathological toxicity. Reflecting the low molecular size of this bispecific engager, PK studies revealed a short plasma half-life which was however compensated for by the prolonged (up to 5 days) binding of the bispecific engager to peripheral blood Vγ9Vδ2-T cells allowing intermittent dosing. Although VHHs have low inherent immunogenicity LAVA-051 was humanized and engineered to avoid binding to pre-existing anti-VHH antibodies that have been reported in ±15% of human individuals and that may limit therapeutic activity. Based on the here reported strong activity against CD1d-expresssing tumors in in vitro, ex vivo and in vivo models and the favorable safety profile of the surrogate engager in NHP, LAVA-051 has been selected for a first-in-human clinical phase 1-2 study in patients with CD1d-expressing, therapy refractory, CLL, MM, or AML. Initiation of this clinical program is scheduled for Q1 2021. Citation Format: Roeland Lameris, Jurjen M. Ruben, Iris de Weerdt, Rob C. Roovers, Arnon P. Kater, Thilo A. Riedl, Victoria Iglesias, Ton Adang, Tanja D. de Gruijl, Paul W.H.I Parren, Hans J. van der Vliet. Potent anti-tumor activity against patient CLL, MM and AML by LAVA-051, a bispecific Vγ9Vδ2-T and type 1 NKT cell engager targeting CD1d [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1855.

Structural and Functional Adaptability of Sucrose and Lactose Permeases from Escherichia coli to the Membrane Lipid Composition.

The lipid environment in which membrane proteins are embedded can influence their structure and function. Lipid-protein interactions and lipid-induced conformational changes necessary for protein function remain intractable in vivo using high-resolution techniques. Using Escherichia coli strains in which the normal phospholipid composition can be altered or foreign lipids can be introduced, we established the importance of membrane lipid composition for the proper folding, assembly, and function of E. coli lactose (LacY) and sucrose (CscB) permeases. However, the molecular mechanism underlying the lipid dependence for active transport remains unknown. Herein, we demonstrate that the structure and function of CscB and LacY can be modulated by the composition of the lipid environment. Using a combination of assays (transport activity of the substrate, protein topology, folding, and assembly into the membrane), we found that alterations in the membrane lipid composition lead to lipid-dependent structural changes in CscB and LacY. These changes affect the orientation of residues involved in LacY proton translocation and impact the rates of protonation and deprotonation of E325 by affecting the arrangement of transmembrane domains in the vicinity of the R302-E325 charge pair. Furthermore, the structural changes caused by changes in membrane lipid composition can be altered by a single-point mutation, highlighting the adaptability of these transporters to their environment. Altogether, our results demonstrate that direct interactions between a protein and its lipid environment uniquely contribute to membrane protein organization and function. Because members of the major facilitator superfamily present with well-conserved functional architecture, we anticipate that our findings can be extrapolated to other membrane protein transporters.

Sclerosing lipogranuloma of the penis: a review of management and classification

Enlargement of penile girth is has always long been a subject of extensive debate and controversy. Genital injection of high-viscosity fluids like paraffin and mineral oil has been performed for more than 100 years. The debilitating effect has been long known, and the procedure has been abandoned by most medical practitioners. Injection often performed by non-professional persons or by the patients themselves, in a non-standardized way. The mineral oil contains foreign lipid that cannot be metabolized by human body, thus foreign body reaction will occur. The inflamed tissue and foreign body reaction will result in sclerosing lipogranuloma. This disorder also known with the injected materials names, e.g. paraffinoma, siliconoma or vaselinoma of the penis. Complications of the injection vary from inflammation, swelling, pain, hardened penile skin, to disastrous effects like ulcers, skin necrosis, pain in erection, sexual disability caused by pain either the patient or the sexual partner, and death by embolism. After injection of the mineral oil, in many patients the symptoms will occur almost instantly. Swelling, inflammation of the penile skin, redness, oedema (that will give an impression of larger penile girth) are among the symptoms occurred. Surgery is the best viable option to treat this disorder. Complete excision of the affected area, followed by covering the healthy area either by grafts or flaps. If available, scrotal skin is a good choice to cover the affected area. A good classification system of sclerosing lipogranuloma of the penis will be helpful in reporting and treating the disease.

Invariant NKT cells facilitate cytotoxic T-cell activation via direct recognition of CD1d on T cells

Invariant natural killer T (iNKT) cells are a major subset of NKT cells that recognize foreign and endogenous lipid antigens presented by CD1d. Although iNKT cells are characteristically autoreactive to self-antigens, the role of iNKT cells in the regulation of cytotoxic T lymphocytes (CTL) has been elucidated using α-galactosylceramide (α-GalCer), a strong synthetic glycolipid that is presented by professional antigen presenting cells (APCs), such as dendritic cells. Despite the well-known effects of α-GalCer and dendritic cells on lipid antigen presentation, the physiological role of endogenous antigens presented by CTLs during crosstalk with iNKT cells has not yet been addressed. In this study, we found that antigen-primed CTLs with transient CD1d upregulation could present lipid self-antigens to activate the iNKT cell production of IFN-γ. CTL-mediated iNKT cell activation in turn enhanced IFN-γ production and the proliferation and cytotoxicity of CTLs. We also found that the direct interaction of iNKT cells and CTLs enhanced the antitumor immune responses of CTLs. This partially explains the functional role of iNKT cells in CTL-mediated antitumor immunity. Our findings suggest that in the absence of exogenous iNKT cell ligands, iNKT cells enhanced the CTL production of IFN-γ and CTL proliferation and cytotoxicity via direct interaction with CD1d expressed on T cells without interacting with APCs.

A T-cell receptor escape channel allows broad T-cell response to CD1b and membrane phospholipids

CD1 proteins are expressed on dendritic cells, where they display lipid antigens to T-cell receptors (TCRs). Here we describe T-cell autoreactivity towards ubiquitous human membrane phospholipids presented by CD1b. These T-cells discriminate between two major types of lipids, sphingolipids and phospholipids, but were broadly cross-reactive towards diverse phospholipids including phosphatidylcholine, phosphatidylinositol and phosphatidylethanolamine. The crystal structure of a representative TCR bound to CD1b-phosphatidylcholine provides a molecular mechanism for this promiscuous recognition. We observe a lateral escape channel in the TCR, which shunted phospholipid head groups sideways along the CD1b-TCR interface, without contacting the TCR. Instead the TCR recognition site involved the neck region phosphate that is common to all major self-phospholipids but absent in sphingolipids. Whereas prior studies have focused on foreign lipids or rare self-lipids, we define a new molecular mechanism of promiscuous recognition of common self-phospholipids including those that are known targets in human autoimmune disease.

The intricacies of self-lipid antigen presentation by CD1b

The CD1 family of glycoproteins are MHC class I-like molecules that present a wide array of self and foreign lipid antigens to T-cell receptors (TCRs) on T-cells. Humans express three classes of CD1 molecules, denoted as Group 1 (CD1a, CD1b, and CD1c), Group 2 (CD1d), and Group 3 (CD1e). Of the CD1 family of molecules, CD1b exhibits the largest and most complex antigen binding groove; allowing it the capabilities to present a broad spectrum of lipid antigens. While its role in foreign-lipid presentation in the context of mycobacterial infection are well characterized, understanding the roles of CD1b in autoreactivity are recently being elucidated. While the mechanisms governing proliferation of CD1b-restricted autoreactive T cells, regulation of CD1 gene expression, and the processes controlling CD1+ antigen presenting cell maturation are widely undercharacterized, the exploration of self-lipid antigens in the context of disease have recently come into focus. Furthermore, the recently expanded pool of CD1b crystal structures allow the opportunity to further analyze the molecular mechanisms of T-cell recognition and self-lipid presentation; where the intricacies of the two-compartment system, that accommodate both the presented self-lipid antigen and scaffold lipids, are scrutinized. This review delves into the immunological and molecular mechanisms governing presentation and T-cell recognition of the broad self-lipid repertoire of CD1b; with evidence mounting pointing towards a role in diseases such as microbial infection, autoimmune diseases, and cancer.

A Subset of Human Autoreactive CD1c-Restricted T Cells Preferentially Expresses TRBV4-1+ TCRs.

In humans, a substantial portion of T cells recognize lipids presented by the monomorphic CD1 proteins. Recent studies have revealed the molecular basis of mycobacterial lipid recognition by CD1c-restricted T cells. Subsets of CD1c-restricted T cells recognize self-lipids in addition to foreign lipids, which may have implications in human diseases involving autoimmunity and malignancy. However, the molecular identity of these self-reactive T cells remains largely elusive. In this study, using a novel CD1c+ artificial APC (aAPC)-based system, we isolated human CD1c-restricted autoreactive T cells and characterized them at the molecular level. By using the human cell line K562, which is deficient in MHC class I/II and CD1 expression, we generated an aAPC expressing CD1c as the sole Ag-presenting molecule. When stimulated with this CD1c+ aAPC presenting endogenous lipids, a subpopulation of primary CD4+ T cells from multiple donors was consistently activated, as measured by CD154 upregulation and cytokine production in a CD1c-specific manner. These activated CD4+ T cells preferentially expressed TRBV4-1+ TCRs. Clonotypic analyses of the reconstituted TRBV4-1+ TCR genes confirmed CD1c-restricted autoreactivity of this repertoire, and the strength of CD1c reactivity was influenced by the diversity of CDR3β sequences. Finally, alanine scanning of CDR1 and CDR2 sequences of TRBV4-1 revealed two unique residues, Arg30 and Tyr51, as critical in conferring CD1c-restricted autoreactivity, thus elucidating the molecular basis of the observed V gene bias. These data provide new insights into the molecular identity of human autoreactive CD1c-restricted T cells.

Sensing Lipids with Mincle: Structure and Function.

Mincle is a C-type lectin receptor that has emerged as an important player in innate immunity through its capacity to recognize a wide range of lipidic species derived from damaged/altered self and foreign microorganisms. Self-ligands include sterols (e.g., cholesterol), and β-glucosylceramides, and the protein SAP130, which is released upon cell death. Foreign lipids comprise those from both microbial pathogens and commensals and include glycerol, glucose and trehalose mycolates, and glycosyl diglycerides. A large effort has focused on structural variation of these ligands to illuminate the structure–activity relationships required for the agonism of signaling though Mincle and has helped identify key differences in ligand recognition between human and rodent Mincle. These studies in turn have helped identify new Mincle ligands, further broadening our understanding of the diversity of organisms and lipidic species recognized by Mincle. Finally, progress toward the development of Mincle agonists as vaccine adjuvants providing humoral and cell-mediated immunity with reduced toxicity is discussed.

Complexity and function of natural killer T cells with potential application to hepatic transplant survival.

One of the major innate-like lymphocyte populations enriched in the liver consists of natural killer T (NKT) cells, which recognize self and foreign lipid antigens presented by the nonpolymorphic class I major histocompatibility complex-like molecule CD1d. NKT cells express natural killer cell markers as well as T cell receptors (TCRs) and can be classified into 2 categories: type I NKT cells use a semi-invariant TCR, whereas type II NKT cells express diverse but still limited TCRs. An emerging body of evidence points to their opposing roles in inflammation, including ischemia/reperfusion injury. Improved understanding of their roles in experimental models as well as in humans and the means by which their function can be manipulated may provide therapeutic benefit in liver diseases and in organ transplantation. Liver Transplantation 23 1589-1592 2017 AASLD.

A Subset of Human Autoreactive CD1c-Restricted T Cells Preferentially Express TRBV4-1+ TCRs and Recognize Phospholipids

Abstract Unlike the highly polymorphic, peptide-presenting conventional MHC molecules, CD1 consists of a family of monomorphic, lipid-presenting proteins. Recent studies have revealed the molecular basis of mycobacterial lipid recognition by CD1a-c-restricted T cells. In addition to foreign lipids, subsets of CD1a-c-restricted T cells recognize self-lipids, which may have implications for human diseases such as autoimmunity and cancer. And yet, the molecular identity of these self-reactive T cells remains largely elusive. In this study, using a novel CD1c+ artificial antigen-presenting cell (aAPC)-based system, we have isolated human CD1c-restricted autoreactive T cells and characterized them at the molecular level. By employing the human cell line K562, deficient in MHC class I/II and CD1 expression, as a backbone, we generated an aAPC expressing CD1c as the sole antigen-presenting molecule with costimulatory molecules, CD80 and CD83. When stimulated with this CD1c+ aAPC endogenously presenting self-lipids, a subpopulation of primary human CD4+ T cells from multiple donors consistently upregulated CD154 (CD40L) in a CD1c-specific manner. These activated CD4+ T cells preferentially expressed TRBV4-1+ TCRs. Interestingly, TRAV usage and CDR3 sequences of these TRBV4-1+ T cells were diverse. Clonotypic analyses of the reconstituted TRBV4-1+ TCRs demonstrated that the heterogeneity of the CDR3 sequences greatly impacted the strength of CD1c-restricted autoreactivity. Furthermore, cell-free assays using recombinant CD1c loaded with distinct lipids identified several phospholipid species as potential self-ligands. These data provide new insights into the molecular identity of human autoreactive CD1c-restricted T cells.

Development and function of skin-homing invariant natural killer T cells

Abstract Invariant natural killer T (iNKT) cells are innate-like T cells that express restricted T cell receptors (TCR) to recognize self and foreign lipid antigens. Distinct iNKT subsets can quickly produce numerous cytokines such as interferon (IFN)-g (iNKT1), interleukin (IL)-4 (iNKT2), and IL-17 (iNKT17) to regulate immune responses in microbial infection, allergic disease, autoimmune disease and cancer. Different iNKT cell subsets have unique transcription factor profiles such as T-bet, PLZF and RORgt that determine their cytokine-producing abilities. However, mechanisms directing the tissue localization preference of different iNKT cell subsets are not well understood. Using a novel strain of CCR10-knockout (KO)/EGFP-knockin (KI) reporter mice, we found that the skin-homing chemokine receptor CCR10 is highly upregulated in iNKT cells during their thymic development stages. Analysis of cytokine production in stimulated thymic iNKT cells demonstrated that CCR10+ iNKT cells are predominantly iNKT2 cells producing IL-4, implying that iNKT2 cells are preferentially programmed in the thymus to migrate into the skin. Confirming this, CCR10-expressing iNKT2 cells are enriched in the skin at the steady state. Taken together, these findings suggest that intrathymic programming orchestrate generation of skin-homing innate-like iNKT cells with specific functional potentials to provide immediate protection of the border tissue.

CD1b-autoreactive T cells recognize phospholipid antigens and contribute to antitumor immunity against a CD1b+ T cell lymphoma

ABSTRACTAdoptive immunotherapy for cancer treatment is an emerging field of study. Till now, several tumor-derived, peptide-specific T cell responses have been harnessed for treating cancers. However, the contribution of lipid-specific T cells in tumor immunity has been understudied. CD1 molecules, which present self- and foreign lipid antigens to T cells, are divided into group 1 (CD1a, CD1b, and CD1c) and group 2 (CD1d). Although the role of CD1d-restricted natural killer T cells (NKT) in several tumor models has been well established, the contribution of group 1 CD1-restricted T cells in tumor immunity remains obscure due to the lack of group 1 CD1 expression in mice. In this study, we used a double transgenic mouse model expressing human group 1 CD1 molecules (hCD1Tg) and a CD1b-restricted, self-lipid reactive T cell receptor (HJ1Tg) to study the potential role of group 1 CD1-restricted autoreactive T cells in antitumor response. We found that HJ1 T cells recognized phospholipids and responded more potently to lipid extracted from tumor cells than the equivalent amount of lipids extracted from normal cells. Additionally, the autoreactivity of HJ1 T cells was enhanced upon treatment with various intracellular toll-like receptor (TLR) agonists, including CpG oligodeoxynucleotides (ODN), R848, and poly (I:C). Interestingly, the adoptive transfer of HJ1 T cells conferred protection against the CD1b-transfected murine T cell lymphoma (RMA-S/CD1b) and CpG ODN enhanced the antitumor effect. Thus, this study, for the first time, demonstrates the antitumor potential of CD1b-autoreactive T cells and their potential use in adoptive immunotherapy.

Natural Killer T cell subsets in eutopic and ectopic endometrium: a fresh look to a busy corner.

Invariant Natural Killer T cells (iNKT) are a specialized subset of T cells that use their T cell receptor to recognize self and foreign lipids presented by CD1d as cognate antigens. iNKT have been shown to have either protective or harmful roles in many pathological states, including microbial infection, autoimmune disease, allergic disease and cancer. Accumulating evidence seems to suggest that this unique T cell subset combines both classically innate and adaptive immunologic characteristic. Considering these recent data, the aim of work was to review the current knowledge about iNKT in eutopic and ectopic endometrium. Narrative overview, synthesizing the findings of literature retrieved from searches of computerized databases. Currently, the immune paradigm of reproduction is gradually changing shape: recent data confirmed that cytokine milieu influences the development and plasticity of different subtype of mononuclear cells, and in turn it can be influenced by the cytokine production of the latter. Among the different NKT cell populations, the recently characterized iNKT seems to share actions typical both of innate and adaptive immunity, being capable of secreting Th1 as well as Th2 cytokine pattern. Moreover, several subtypes of iNKT were identified, who partially express the same master transcription factors of the corresponding T cells counterpart. Although the data about iNKT's actions in eutopic and ectopic endometrium are still scarce, it is possible to hypothesize that future investigation can shed light on this point, thus allowing a better knowledge about the regulation of these two microenvironments.

Activation of human T cells by CD1 and self-lipids.

Over two decades ago, it was discovered that the human T-cell repertoire contains T cells that do not recognize peptide antigens in the context of MHC molecules but instead respond to lipid antigens presented by CD1 antigen-presenting molecules. The ability of T cells to 'see' lipid antigens bound to CD1 enables these lymphocytes to sense changes in the lipid composition of cells and tissues as a result of infections, inflammation, or malignancies. Although foreign lipid antigens have been shown to function as antigens for CD1-restricted T cells, many CD1-restricted T cells do not require foreign antigens for activation but instead can be activated by self-lipids presented by CD1. This review highlights recent developments in the field, including the identification of common mammalian lipids that function as autoantigens for αβ and γδ T cells, a novel mode of T-cell activation whereby CD1a itself rather than lipids serves as the autoantigen, and various mechanisms by which the activation of CD1-autoreactive T cells is regulated. As CD1 can induce T-cell effector functions in the absence of foreign antigens, multiple mechanisms are in place to regulate this self-reactivity, and stimulatory CD1-lipid complexes appear to be tightly controlled in space and time.

Lymphocytes in atherosclerosis.

Atherosclerosis is the major cause of cardiovascular disease, and cardiovascular disease remains the primary cause of death in the United States. The primary complication for patients with type 2 diabetes mellitus (T2D) is cardiovascular disease.1–8 Because the incidences of T2D and obesity are drastically increasing in the United States and now worldwide, understanding how atherosclerosis is accelerated in these diseases becomes even more important to discern. Although many scientific advances in research on atherosclerosis have been made by multiple groups during the past 30 years, particularly about the function of endothelial and smooth muscle biology and macrophage foam cell formation in atherosclerotic plaque development, the roles of immune cells in regulating atherosclerosis onset and progression are still being elucidated. It was widely thought that immune cells played little part in atherogenesis until 1986, when Hansson et al9–12 reported the presence of lymphocytes within atherosclerotic lesions; yet it was many years later until it was widely accepted that immune cells play an important role in atherogenesis. Since 1986, the viewpoint has changed significantly, but details on lymphocyte subsets and mechanisms are still emerging. Moreover, controversy still exists on the roles that some lymphocyte subsets play in atherosclerosis. These discrepancies in findings are at least partly because of differences in mouse models used, diet composition, and length of time on diet for atherosclerosis measurements. However, despite a few ongoing controversies, there are many studies on immune cells in atherogenesis in mice that show clear findings.10,12–23 For example, CD4+ T lymphocytes have been shown to accelerate atherosclerosis.18,24–29 Activated CD4 T cells can be distinguished based on their phenotype, and the predominant CD4+ effector T cells studied to date in the context of atherosclerosis are Th1, …