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12.3E: Invarient Natural Killer T-Lymphocytes (iNKT Cells)

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  • Learning Objectives

    1. Describe the overall function of iNKT cells and their activation in terms of the following:
      1. the role of their TCRs
      2. how they are activated by antigen-presenting cells
      3. how they promote both innate and adaptive immunity and may also help to regulate the immune responses

    Invariant Natural Killer T-lymphocytes (iNKT Cells) cells are a subset of lymphocytes that bridge the gap between innate and adaptive immunity. They have T-cell receptors (TCRs) on their surface for glycolipid antigen recognition. They also have natural killer (NK) cell receptors. NK cells are discussed later in this unit. Through the cytokines they produce once activated, iNKT cells are essential in both innate and adaptive immune protection against pathogens and tumors. They also play a regulatory role in the development of autoimmune diseases, asthma, and transplantation tolerance. It has been shown that iNKT cell deficiency or disfunction can lead to the development of autoimmune diseases, human asthma, and cancers.

    Pathogens may not directly activate iNKT cells. The TCR of iNKT cells recognize exogenous glycolipid antigens, as well as endogenous self glycolipid antigens presented by MHC-I-like CD1d molecules on antigen presenting dendritic cells. Antigen-presenting dendritic cells engulf glycolipids from certain microorganisms (exogenous glycolipids) and degrade them with their lysosomes (Figure \(\PageIndex{1}\)). Dendritic cells also engulf certain glycolipids from human cells (endogenous glycolipids) and degrade them with their lysosomes (Figure \(\PageIndex{2}\)). These glycolipid epitopes are then bound to CD1d molecules produced by dendritic cells and transported to the surface of the cell where they can be presented to the TCR of iNKT cells to induce iNKT cell activation (Figure \(\PageIndex{1}\) and Figure \(\PageIndex{2}\)). iNKT cells can also be activated by the cytokine Interleukin-12 (IL-12) produced by dendritic cells that have themselves become activated by pathogen-associated molecular patterns (PAMPs) of microbes binding to the pattern-recognition receptors (PRRs) of the dendritic cell (Figure \(\PageIndex{3}\)).


    Figure \(\PageIndex{1}\): An iNKT-Lymphocyte Recognizing Microbial Glycolipid Antigen Bound to a CD1d Molecule on a Dendritic Cell. 1. Antigen-presenting dendritic cells engulf certain microbes or microbial glycolipids (exogenous glycolipids). 2. The glycolipids are degrade into epitopes by lysosomes. 3. The glycolipid epitopes are then bound to CD1d molecules produced in the endoplasmic reticulum by the dendritic cell. 4. The glycolipid epitope/CD1d complexs are transported by the Golgi apparatus to the surface of the dendritic cell. 5. Here the glycolipid epitope can be presented to theTCR of iNKT cells to induce iNKT cell activation.

    Once activated, the iNKT cells rapidly produce large quantities of both TH1 cell and TH2 cell cytokines, including interferon-gamma (IFN-?), interleukin-4 (IL-4), interleukin-2 (IL-2), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-a), interleukin-13 (IL-13), and chemokines. Through the rapid productions of such cytokines, iNKT cells are able to promote and suppress different innate and adaptive immune responses. For example, large amounts of IFN-? are produced by activated iNKT cells. IFN-? activates NK cells and macrophages as a part of innate immunity; it also promotes the maturation of dendritic cells so that they induce a TH1 cell response to induce adaptive immunity.

    It has been proposed that if the iNKT cell is repeatedly stimulated by the body's own glycolipids in the ab sense of microbes that this might stimulate the iNKT cell /dendritic cell interaction to produce tolerizing signals that inhibit the TH1 cell response and possibly stimulate the production of regulatory T-lymphocytes (Treg cells). In this way it might suppress autoimmune responses and prevent tissue damage.

    There is also growing evidence that early childhood exposure to microbes is associated with protection against allergic diseases, asthma, and inflammatory diseases such as ulcerative colitis. It has been found that germ-free mice have large accumulations of mucosal iNKT cells in the lungs and intestines and increased morbidity from allergic asthma and inflammatory bowel disease. However, colonization of neonatal germ-free mice with normal microbiota resulted in mucosal iNKT cell tolerance to these diseases. It has been proposed that microbes the human body has been traditionally exposed to from early childhood throughout most of human history might play a role in developing normal iNKT cell numbers and iNKT cell responses.

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