Shilpi Chandra

Activation and Function of iNKT and MAIT Cells

Over the last two decades, it has been established that peptides are not the only antigens recognized by T lymphocytes. Here, we review information on two T lymphocyte populations that recognize nonpeptide antigens: invariant natural killer T cells (iNKT cells), which respond to glycolipids, and mucosal associated invariant T cells (MAIT cells), which recognize microbial metabolites. These two populations have a number of striking properties that distinguish them from the majority of T cells. First, their cognate antigens are presented by nonclassical class I antigen-presenting molecules; CD1d for iNKT cells and MR1 for MAIT cells. Second, these T lymphocyte populations have a highly restricted diversity of their T cell antigen receptor α chains. Third, these cells respond rapidly to antigen or cytokine stimulation by producing copious amounts of cytokines, such as IFNγ, which normally are only made by highly differentiated effector T lymphocytes. Because of their response characteristics, iNKT and MAIT cells act at the interface of innate and adaptive immunity, participating in both types of responses. In this review, we will compare these two subsets of innate-like T cells, with an emphasis on the various ways that lead to their activation and their participation in antimicrobial responses.

A new mouse strain for the analysis of invariant NKT cell function.

1 suppressed in the available strain of mice with deletion of the Traj18 gene segment6. In this strain, the gene encoding the neomycin-resistance selection marker, driven by the promoter of the phosphoglycerate kinase gene (Pgkneor), is not removed. Therefore, the authors proposed that the transcription of Pgk-neor, which is in an orientation opposite to that of the Jα regions, led to the suppression of rearrangement of the majority of Jα regions and thereby caused substantial distortion of the TCRα repertoire. Here we describe a new mouse strain with deletion of Traj18 created on the C57BL/6 background in which neor was deleted along with the Traj18 gene segment. These crucial influence on a wide variety of immune and inflammatory responses2. Mice deficient in iNKT cells provide a key tool for analysis of the role of these cells in various contexts. There are two widely used mouse models of iNKT cell deficiency, but neither provides a completely specific defect. Mice lacking the Cd1d1 and Cd1d2 loci cannot positively select iNKT cells, but they also do not have type II NKT cells3, which are CD1d-reactive T lymphocytes with a more diverse α-chain repertoire4. Mice lacking the Traj18 gene segment cannot form the TCRα chain that is essential for iNKT cell development5. However, a published study has reported that rearrangements of all the Jα regions upstream of Traj18 were To the editor: Invariant natural killer T cells (iNKT cells) are a T lymphocyte population with restricted T cell antigen receptor (TCR) diversity. They make up a distinct subset of T lymphocytes that is activated by glycolipid antigens presented by CD1d, a non-classical major histocompatibility complex class I–like molecule. The invariant TCR of iNKT cells consists of a specific α-chain rearrangement, of α-chain variable region 14 and α-chain joining region 18 (Vα14-Jα18), encoded by Tcra gene segments Trav11-Traj18 in mice, and Vα24-Jα18 (TRAV10-TRAJ18) in humans, and a limited β-chain repertoire1. iNKT cells are associated with early immune responses and have been reported to exert a A new mouse strain for the analysis of invariant NKT cell function

Development of Asthma in Inner-City Children: Possible Roles of MAIT Cells and Variation in the Home Environment

Humans have populations of innate-like T lymphocytes with an invariant TCR α-chain that recognize nonpeptide Ags, including invariant NKT (iNKT) cells and mucosal-associated invariant T (MAIT) cells. iNKT cell involvement in human asthma is controversial, whereas there has been little analysis of MAIT cells. Using peripheral blood cells from 110 participants from the Urban Environment and Childhood Asthma (URECA) birth cohort study, these cells were analyzed for number and function. We determined whether iNKT cell or MAIT cell frequency at 1 y is correlated with the cytokine polarization of mainstream CD4+ T cells and/or the development of asthma by age 7 y. Dust samples from 300 houses were tested for iNKT cell antigenic activity. Our results show that a higher MAIT cell frequency at 1 y of age was associated with a decreased risk of asthma by age 7 y. The frequency of MAIT cells was associated with increased production of IFN-γ by activated CD4+ T cells from the URECA cohort. iNKT cell antigenic activity in bedroom dust samples was associated with higher endotoxin concentration and also with reduced risk of asthma. In conclusion, MAIT cell frequency at 1 y may reflect the tendency of the immune system toward Th1 responses and is associated with protection from asthma. Additionally, iNKT cell antigenic activity may be a marker of houses with increased microbial exposures and therefore also with protection from asthma.

CD1d-restricted peripheral T cell lymphoma in mice and humans

Genestier et al. shed light on the cellular origin of peripheral T cell lymphoma (PTCL), showing that in both mice and humans, unconventional CD1d-restricted T cells may give rise to PTCL.

ATP Binding Cassette Transporter ABCA7 Regulates NKT Cell Development and Function by Controlling CD1d Expression and Lipid Raft Content.

ABCA7 is an ABC transporter expressed on the plasma membrane, and actively exports phospholipid complexes from the cytoplasmic to the exocytoplasmic leaflet of membranes. Invariant NKT (iNKT) cells are a subpopulation of T lymphocytes that recognize glycolipid antigens in the context of CD1d-mediated antigen presentation. In this study, we demonstrate that ABCA7 regulates the development of NKT cells in a cell-extrinsic manner. We found that in Abca7−/− mice there is reduced expression of CD1d accompanied by an alteration in lipid raft content on the plasma membrane of thymocytes and antigen presenting cells. Together, these alterations caused by absence of ABCA7 negatively affect NKT cell development and function.

Response to Comment on “Development of Asthma in Inner-City Children: Possible Roles of MAIT Cells and Variation in the Home Environment”

We appreciate that G. Lezmi and M. Leite-de-Moraes called attention to our recent publication ([1][1]) on mucosal-associated invariant T (MAIT) cells and childhood asthma. We are pleased that their interesting, recent work also finds a link between MAIT cells and this disease. This is logical,

Differential Role of Cathepsins S and B In Hepatic APC-Mediated NKT Cell Activation and Cytokine Secretion

Natural killer T (NKT) cells exhibit a specific tissue distribution, displaying the liver the highest NKT/conventional T cell ratio. Upon antigen stimulation, NKT cells secrete Th1 cytokines, including interferon γ (IFNγ), and Th2 cytokines, including IL-4 that recruit and activate other innate immune cells to exacerbate inflammatory responses in the liver. Cysteine cathepsins control hepatic inflammation by regulating κB-dependent gene expression. However, the contribution of cysteine cathepsins other than Cathepsin S to NKT cell activation has remained largely unexplored. Here we report that cysteine cathepsins, cathepsin B (CTSB) and cathepsin S (CTSS), regulate different aspects of NKT cell activation. Inhibition of CTSB or CTSS reduced hepatic NKT cell expansion in a mouse model after LPS challenge. By contrast, only CTSS inhibition reduced IFNγ and IL-4 secretion after in vivo α-GalCer administration. Accordingly, in vitro studies reveal that only CTSS was able to control α-GalCer-dependent loading in antigen-presenting cells (APCs), probably due to altered endolysosomal protein degradation. In summary, our study discloses the participation of cysteine cathepsins, CTSB and CTSS, in the activation of NKT cells in vivo and in vitro.

LIGHT-HVEM Signaling in Innate Lymphoid Cell Subsets Protects Against Enteric Bacterial Infection

Innate lymphoid cells (ILCs) are important regulators of early infection at mucosal barriers. ILCs are divided into three groups based on expression profiles, and are activated by cytokines and neuropeptides. Yet, it remains unknown if ILCs integrate other signals in providing protection. We show that signaling through herpes virus entry mediator (HVEM), a member of the tumor necrosis factor (TNF) receptor superfamily, in ILC3 is important for host defense against oral infection with the bacterial pathogen Yersinia enterocolitica. HVEM stimulates protective interferon-γ (IFN-γ) secretion from ILCs, and mice with HVEM-deficient ILC3 exhibit reduced IFN-γ production, higher bacterial burdens and increased mortality. In addition, IFN-γ production is critical as adoptive transfer of wild-type but not IFN-γ-deficient ILC3 can restore protection to mice lacking ILCs. We identify the TNF superfamily member, LIGHT, as the ligand inducing HVEM signals in ILCs. Thus HVEM signaling mediated by LIGHT plays a critical role in regulating ILC3-derived IFN-γ production for protection following infection. VIDEO ABSTRACT.

Mrp1 is involved in lipid presentation and iNKT cell activation by Streptococcus pneumoniae

Invariant natural killer T cells (iNKT cells) are activated by lipid antigens presented by CD1d, but the pathway leading to lipid antigen presentation remains incompletely characterized. Here we show a whole-genome siRNA screen to elucidate the CD1d presentation pathway. A majority of gene knockdowns that diminish antigen presentation reduced formation of glycolipid-CD1d complexes on the cell surface, including members of the HOPS and ESCRT complexes, genes affecting cytoskeletal rearrangement, and ABC family transporters. We validated the role in vivo for the multidrug resistance protein 1 (Mrp1) in CD1d antigen presentation. Mrp1 deficiency reduces surface clustering of CD1d, which decreased iNKT cell activation. Infected Mrp1 knockout mice show decreased iNKT cell responses to antigens from Streptococcus pneumoniae and were associated with increased mortality. Our results highlight the unique cellular events involved in lipid antigen presentation and show how modification of this pathway can lead to lethal infection.The CD1d pathway present lipid antigens resulting in the activation of iNKT cells but the complete pathway remains to be fully elucidated. Here, Chandra et al. use an siRNA screen and identify Mrp1 as crucial for CD1d lipid presentation and activation of iNKT in the context of Streptococcus pneumoniae infection.

Cysteine Cathepsins are Involved in a Double Check-Point during Hepatic NKT Activation

Trabajo presentado en el International Liver Congress, celebrado en Barcelona, Espana, del 13 al 17 de abril de 2016