Role of NKT Cells in the Digestive System. III. Role of NKT cells in intestinal immunity

Natural killer T (NKT) cells are a small subset of unconventional T cells that recognize lipid antigens presented by the nonclassical major histocompatibility complex (MHC) class I molecule CD1d. NKT cells are involved in the host response to a variety of microbial pathogens and likely commensals. In the intestine, invariant and noninvariant NKT cells can be found among intraepithelial lymphocytes and in the lamina propria. Activation of intestinal NKT cells by CD1d-expressing intestinal epithelial cells and professional antigen-presenting cells may contribute to induction of oral tolerance and protection from mucosal infections. On the other hand, sustained and uncontrolled activation of NKT cells may play a pivotal role in the pathogenesis of inflammatory bowel disease. Here we review the current literature on intestinal NKT cells and their function in the intestine in health and disease.

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Microenvironmental Metabolites in the Intestine: Messengers between Health and Disease

Metabolites ◽

10.3390/metabo12010046 ◽

2022 ◽

Vol 12 (1) ◽

pp. 46

Author(s):

Antonio Enrico Zaurito ◽

Markus Tschurtschenthaler

Keyword(s):

Communication Systems ◽

Intestinal Inflammation ◽

Intestinal Epithelial ◽

Intestinal Immunity ◽

Extrinsic Factors ◽

Colorectal Tumorigenesis ◽

Molecular Communication Systems ◽

Health And Disease ◽

Inflammatory Bowel

The intestinal mucosa is a highly absorptive organ and simultaneously constitutes the physical barrier between the host and a complex outer ecosystem. Intestinal epithelial cells (IECs) represent a special node that receives signals from the host and the environment and translates them into corresponding responses. Specific molecular communication systems such as metabolites are known to transmit information across the intestinal boundary. The gut microbiota or food-derived metabolites are extrinsic factors that influence the homeostasis of the intestinal epithelium, while mitochondrial and host-derived cellular metabolites determine the identity, fitness, and regenerative capacity of IECs. Little is known, however, about the role of intrinsic and extrinsic metabolites of IECs in the initiation and progression of pathological processes such as inflammatory bowel disease and colorectal cancer as well as about their impact on intestinal immunity. In this review, we will highlight the most recent contributions on the modulatory effects of intestinal metabolites in gut pathophysiology, with a particular focus on metabolites in promoting intestinal inflammation or colorectal tumorigenesis. In addition, we will provide a perspective on the role of newly identified oncometabolites from the commensal and opportunistic microbiota in shaping response and resistance to antitumor therapy.

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Thymus leukemia antigen controls intraepithelial lymphocyte function and inflammatory bowel disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0808242105 ◽

2008 ◽

Vol 105 (46) ◽

pp. 17931-17936 ◽

Cited By ~ 38

Author(s):

Danyvid Olivares-Villagómez ◽

Yanice V. Mendez-Fernandez ◽

Vrajesh V. Parekh ◽

Saif Lalani ◽

Tiffaney L. Vincent ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Genetic Model ◽

Critical Role ◽

Intraepithelial Lymphocytes ◽

Lymphocyte Function ◽

Intestinal Epithelial ◽

Inflammatory Bowel

Intestinal intraepithelial lymphocytes (IEL) bear a partially activated phenotype that permits them to rapidly respond to antigenic insults. However, this phenotype also implies that IEL must be highly controlled to prevent misdirected immune reactions. It has been suggested that IEL are regulated through the interaction of the CD8αα homodimer with the thymus leukemia (TL) antigen expressed by intestinal epithelial cells. We have generated and characterized mice genetically-deficient in TL expression. Our findings show that TL expression has a critical role in maintaining IEL effector functions. Also, TL deficiency accelerated colitis in a genetic model of inflammatory bowel disease. These findings reveal an important regulatory role of TL in controlling IEL function and intestinal inflammation.

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Invariant NKT Cells Regulate Osteoclast Development and Function Under Homeostatic and during Conditions of Immune Activation

Blood ◽

10.1182/blood.v112.11.104.104 ◽

2008 ◽

Vol 112 (11) ◽

pp. 104-104

Author(s):

Ming Hu ◽

J.H. Duncan Basssett ◽

Lynette Danks ◽

Emmanouil Spanoudakis ◽

Ke Xu ◽

...

Keyword(s):

Immune Responses ◽

Nkt Cells ◽

Innate Immune ◽

Small Subset ◽

Developmental Defect ◽

Invariant Nkt Cells ◽

And Function ◽

Actin Rings

Abstract Invariant NKT cells, a small subset of immunoregulatory T cells restricted by the glycolipid-presenting non-polymorphic CD1d molecule, are able to modulate a variety of innate and adaptive immune responses. Osteoclasts (OC) are bone resorbing polykaryons of hematopoietic lineage, that have the capacity to regulate myeloid cell egress from bone marrow (BM) thus making them an integral part of the innate immune response. We and others previously showed that NKT cells regulate hematopoiesis in mice as well as humans. In this work, we investigate the role of NKT cells in OC development and function in homeostasis and after their specific activation by the model glycolipid alpha-galactosylceramide (aGC). Using quantitative back scattered electron scanning microscopy, we found that TCR Ja18 −/− mice which selectively lack development of NKT cells, exhibit a moderate osteopetrotic phenotype affecting trabecular as well as cortical bone. Histologically, these mice had the same number of TRAP+ OC as WT mice suggesting a maturation rather developmental defect in the TCR Ja18 −/−-derived OC. In vitro differentiation in the presence of RANKL and M-CSF showed that while TCR Ja18 −/− BM cells are capable of forming multinucleated OC, these, as assessed by confocal microscopy, fail to form F-actin rings and sealing zone and thus are unable to resorb bone. Further underscoring the effect of NKT cells in this process, CD45.1+ BM cells highly purified from CD45.2+ WT/CD45.1+ TCRJa18 −/− mixed BM chimeras displayed restoration of their OC F-actin rings. Next we investigated whether in vivo activated NKT cells regulate OC function. We found that a single injection of aGC dramatically increased the number of CD3-B220-CD11b-c-fmshighc- kithigh BM OC progenitors and accelerated the in vitro development of OC in WT but not TCR Ja18 −/− mice. Furthermore, this resulted in high serum levels of IFN-g and IL-4 but not IL-1 or IL-17. An aGC-mediated increase of OC progenitors was observed in IFN-g −/− but not IL-4 −/−mice suggesting that NKT cell-derived IL-4 is the main cytokine promoting osteoclastogenesis in this context. Taken together, our data demonstrate a novel role of NKT cells in homeostatic bone mass regulation and in the orchestration of innate immune responses through regulation of OC development and function.

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Gut epithelial IL-27 confers intestinal immunity through the induction of intraepithelial lymphocytes

Journal of Experimental Medicine ◽

10.1084/jem.20210021 ◽

2021 ◽

Vol 218 (11) ◽

Author(s):

Chia-Hao Lin ◽

Mei-Chi Chen ◽

Ling-Li Lin ◽

David A. Christian ◽

Booki Min ◽

...

Keyword(s):

Parasitic Infection ◽

Cell Types ◽

Functional Differentiation ◽

Intraepithelial Lymphocytes ◽

Intestinal Epithelial ◽

Intestinal Immunity ◽

Diverse Range ◽

Pathogen Burden ◽

Different Cell Types ◽

Barrier Immunity

IL-27 controls a diverse range of immune responses in many disease settings. Here, we identify intestinal epithelial cells (IECs) as one of the major IL-27 cellular sources in the gut-associated tissue. Unlike IL-27 secreted by innate immune cells, gut epithelial IL-27 is dispensable for T-bet+ regulatory T cell (T reg cell) differentiation or IL-10 induction. Rather, IEC-derived IL-27 specifically promotes a distinct CD8αα+CD4+ intraepithelial lymphocyte (IEL) population that acquires their functional differentiation at the intestinal epithelium. Loss of IL-27 in IECs leads to a selective defect in CD8αα+CD4+ IELs over time. Consequently, mice with IEC-specific IL-27 ablation exhibited elevated pathogen burden during parasitic infection, and this could be rescued by transfer of exogenous CD8αα+CD4+ IELs. Collectively, our data reveal that in addition to its known regulatory properties in preventing immune hyperactivity, gut epithelial IL-27 confers barrier immunity by inducing a specific IEL subset and further suggest that IL-27 produced by different cell types plays distinct roles in maintaining intestinal homeostasis.

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Distinct CD1d docking strategies exhibited by diverse Type II NKT cell receptors

Nature Communications ◽

10.1038/s41467-019-12941-9 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 4

Author(s):

Catarina F. Almeida ◽

Srinivasan Sundararaj ◽

Jérôme Le Nours ◽

T. Praveena ◽

Benjamin Cao ◽

...

Keyword(s):

Nkt Cells ◽

Type I ◽

Type Ii ◽

Nkt Cell ◽

Lipid Antigens ◽

Microbial Antigen ◽

Health And Disease ◽

Lipid Antigen ◽

And Function ◽

Antigen Presenting

AbstractType I and type II natural killer T (NKT) cells are restricted to the lipid antigen-presenting molecule CD1d. While we have an understanding of the antigen reactivity and function of type I NKT cells, our knowledge of type II NKT cells in health and disease remains unclear. Here we describe a population of type II NKT cells that recognise and respond to the microbial antigen, α-glucuronosyl-diacylglycerol (α-GlcADAG) presented by CD1d, but not the prototypical type I NKT cell agonist, α-galactosylceramide. Surprisingly, the crystal structure of a type II NKT TCR-CD1d-α-GlcADAG complex reveals a CD1d F’-pocket-docking mode that contrasts sharply with the previously determined A’-roof positioning of a sulfatide-reactive type II NKT TCR. Our data also suggest that diverse type II NKT TCRs directed against distinct microbial or mammalian lipid antigens adopt multiple recognition strategies on CD1d, thereby maximising the potential for type II NKT cells to detect different lipid antigens.

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T cell receptor is required for differentiation but not maintenance of intestinal intraepithelial lymphocytes

10.1101/2020.06.04.134510 ◽

2020 ◽

Author(s):

Angelina M. Bilate ◽

Mariya London ◽

Tiago B. R. Castro ◽

Luka Mesin ◽

Suppawat Kongthong ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Intraepithelial Lymphocytes ◽

Intestinal Epithelial ◽

Conditional Deletion ◽

Tcr Repertoire ◽

Regulatory Properties

SummaryThe gut epithelium is populated by intraepithelial lymphocytes (IELs), a heterogeneous T cell population with cytotoxic and regulatory properties. Migrating peripheral CD4+ T cells, including regulatory (Treg) and conventional T cells (Tconv), acquire an IEL (CD4-IEL) program upon arrival at the epithelium. However, the specific role of the T cell receptor (TCR) in this process remains unclear. Single-cell TCR repertoire and transcriptomic analysis of intraepithelial CD4+ T cells revealed different extents of clonal expansion and TCR overlap between cell states; fully differentiated CD4-IELs from Tregs or Tconvs were the least diverse. Conditional deletion of TCR on differentiating CD4+ T cells or of MHCII on intestinal epithelial cells prevented CD4-IEL differentiation. However, TCR ablation on developed CD4-IELs did not affect their accumulation. These results indicate that local recognition of a limited set of antigens is an essential signal for the differentiation and adaptation of T cells to the epithelium.

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Implication of Fructans in Health: Immunomodulatory and Antioxidant Mechanisms

The Scientific World JOURNAL ◽

10.1155/2015/289267 ◽

2015 ◽

Vol 2015 ◽

pp. 1-15 ◽

Cited By ~ 38

Author(s):

Elena Franco-Robles ◽

Mercedes G. López

Keyword(s):

Short Chain Fatty Acids ◽

The Body ◽

Intestinal Lumen ◽

Immunomodulatory Activity ◽

Intestinal Epithelial ◽

Intestinal Immune System ◽

Glucose Molecule ◽

Health And Disease ◽

Antioxidant Mechanisms

Previous studies have shown that fructans, a soluble dietary fiber, are beneficial to human health and offer a promising approach for the treatment of some diseases. Fructans are nonreducing carbohydrates composed of fructosyl units and terminated by a single glucose molecule. These carbohydrates may be straight or branched with varying degrees of polymerization. Additionally, fructans are resistant to hydrolysis by human digestive enzymes but can be fermented by the colonic microbiota to produce short chain fatty acids (SCFAs), metabolic by-products that possess immunomodulatory activity. The indirect role of fructans in stimulating probiotic growth is one of the mechanisms through which fructans exert their prebiotic activity and improve health or ameliorate disease. However, a more direct mechanism for fructan activity has recently been suggested; fructans may interact with immune cells in the intestinal lumen to modulate immune responses in the body. Fructans are currently being studied for their potential as “ROS scavengers” that benefit intestinal epithelial cells by improving their redox environment. In this review, we discuss recent advances in our understanding of fructans interaction with the intestinal immune system, the gut microbiota, and other components of the intestinal lumen to provide an overview of the mechanisms underlying the effects of fructans on health and disease.

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The Prevalence of Gingival Dendritic Cell Subsets in Periodontal Patients

Journal of Dental Research ◽

10.1177/00220345211004864 ◽

2021 ◽

pp. 002203452110048

Author(s):

H. Sharawi ◽

O. Heyman ◽

G. Mizraji ◽

Y. Horev ◽

A. Laviv ◽

...

Keyword(s):

Periodontal Diseases ◽

Mononuclear Phagocytes ◽

Human Gingiva ◽

Physiological Homeostasis ◽

Health And Disease ◽

And Function ◽

Antigen Presenting ◽

The Impact

As the most potent cells activating and polarizing naive T cells, dendritic cells (DCs) are of major importance in the induction of immunity and tolerance. DCs are a heterogeneous population of antigen-presenting cells that are widely distributed in lymphoid and nonlymphoid tissues. Murine studies have highlighted the important role of oral DCs and Langerhans cells (LCs) in orchestrating the physiological homeostasis of the oral mucosa. DCs are also critically involved in pathological conditions such as periodontal diseases, in which gingival DCs appear to have special localization and function. While the characterization of human DCs in health and disease has been extensively investigated in various tissues, this topic was rarely studied in human gingiva. Here, we employed an up-to-date approach to characterize by flow cytometry the gingival DCs of 27 healthy subjects and 21 periodontal patients. Four distinct subsets of mononuclear phagocytes were identified in healthy gingiva: conventional DC type 1 (cDC1), cDC2, plasmacytoid DCs (pDCs), and LCs. In periodontitis patients, the frequencies of gingival LCs and pDCs were dysregulated, as LCs decreased, whereas pDCs increased in the diseased gingiva. This shift in the prevalence of DCs was accompanied by increased expression of the proinflammatory cytokines interleukin (IL)–1β, interferon (IFN)–α, and IFN-γ, while the anti-inflammatory cytokine IL-10 was suppressed. We further found that smoking, a known risk factor of periodontitis, specifically reduces gingival LCs in healthy individuals, indicating a possible role of LCs in the elevated severity of periodontitis in smokers. Collectively, this work reveals the various DC subsets residing in the human gingiva and the impact of periodontitis, as well as smoking, on the prevalence of each subset. Our findings provide a foundation toward understanding the role of human DCs in orchestrating physiological oral immunity and set the stage for the evaluation and modulation of shifts in immunity associated with periodontitis.

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Natural Killer T (NKT) Cells and Periodontitis: Potential Regulatory Role of NKT10 Cells

Mediators of Inflammation ◽

10.1155/2021/5573937 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Samanta Melgar-Rodríguez ◽

Emilio A. Cafferata ◽

Nicolás I. Díaz ◽

Miguel A. Peña ◽

Luis González-Osuna ◽

...

Keyword(s):

Immune Responses ◽

Natural Killer ◽

Inflammatory Diseases ◽

Nkt Cells ◽

Regulatory Role ◽

Th17 Lymphocytes ◽

Antigen Presenting ◽

Potential Regulatory Role ◽

Natural Killer T

Natural killer T (NKT) cells constitute a unique subset of T lymphocytes characterized by specifically interacting with antigenic glycolipids conjugated to the CD1d receptor on antigen-presenting cells. Functionally, NKT cells are capable of performing either effector or suppressor immune responses, depending on their production of proinflammatory or anti-inflammatory cytokines, respectively. Effector NKT cells are subdivided into three subsets, termed NKT1, NKT2, and NKT17, based on the cytokines they produce and their similarity to the cytokine profile produced by Th1, Th2, and Th17 lymphocytes, respectively. Recently, a new subgroup of NKT cells termed NKT10 has been described, which cooperates and interacts with other immune cells to promote immunoregulatory responses. Although the tissue-specific functions of NKT cells have not been fully elucidated, their activity has been associated with the pathogenesis of different inflammatory diseases with immunopathogenic similarities to periodontitis, including osteolytic pathologies such as rheumatoid arthritis and osteoporosis. In the present review, we revise and discuss the pathogenic characteristics of NKT cells in these diseases and their role in the pathogenesis of periodontitis; particularly, we analyze the potential regulatory role of the IL-10-producing NKT10 cells.

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Role of NKT cells in the digestive system. IV. The role of canonical natural killer T cells in mucosal immunity and inflammation

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00437.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. G1-G8 ◽

Cited By ~ 39

Author(s):

Gerhard Wingender ◽

Mitchell Kronenberg

Keyword(s):

T Cells ◽

Natural Killer ◽

Nkt Cells ◽

Mucosal Tissues ◽

And Function ◽

Antigen Presenting ◽

Killer T Cells ◽

Two Populations ◽

Natural Killer T

Lymphocytes that combine features of T cells and natural killer (NK) cells are named natural killer T (NKT) cells. The majority of NKT cells in mice bear highly conserved invariant Vα chains, and to date two populations of such canonical NKT cells are known in mice: those that express Vα14 and those that express Vα7.2. Both populations are selected by nonpolymorphic major histocompatibility complex class I-like antigen-presenting molecules expressed by hematopoietic cells in the thymus: CD1d for Vα14-expressing NKT cells and MR1 for those cells expressing Vα7.2. The more intensely studied Vα14 NKT cells have been implicated in diverse immune reactions, including immune regulation and inflammation in the intestine; the Vα7.2 expressing cells are most frequently found in the lamina propria. In humans, populations of canonical NKT cells are found to be highly similar in terms of the expression of homologous, invariant T cell antigen-receptor α-chains, specificity, and function, although their frequency differs from those in the mouse. In this review, we will focus on the role of both of these canonical NKT cell populations in the mucosal tissues of the intestine.

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