Natural Killer Cells

A blogger, Dr. Andy, who is an allergist/immunologist at the Children's Hospital of Pittsburg, has written an interesting item on Natural Killer Cells. More cool immune system evolution or, how did an inhibitory receptor turn into a activating one?

NK (natural killer) cells are a special kind of white blood cell that specialize in killing tumor and virally infected cells. Unlike T and B cells they can’t shuffle segments of DNA to generated diverse antigen receptors (antibodies from B cells and T cell receptors) to recognize “foreign" material. Instead they integrate signals through a number of cell surface receptors to make a decision about whether or not to lyse another cell. You can read the rest of this article here: doctorandy.blogspot.com/2005/05/more-cool-immune-system-evolution.html or www.nature.com/cgi-taf/DynaPage.taf?file=/nri/journal/v5/n5/abs/nri1603_fs.html

A NEW SELF: MHC-CLASS-I-INDEPENDENT NATURAL-KILLER-CELL SELF-TOLERANCE

Vinay Kumar & Megan E. McNerney (Abstract)

A fundamental tenet of the immune system is the requirement for lymphocytes to respond to transformed or infected cells while remaining tolerant of normal cells. Natural killer (NK) cells discriminate between self and non-self by monitoring the expression of MHC class I molecules. According to the 'missing-self' hypothesis, cells that express self-MHC class I molecules are protected from NK cells, but those that lack this self-marker are eliminated by NK cells. Recent work has revealed that there is another system of NK-cell inhibition, which is independent of MHC class I molecules. Newly discovered NK-cell inhibitory receptors that have non-MHC-molecule ligands broaden the definition of self as seen by NK cells.

Summary

• Natural killer (NK) cell cytotoxicity is regulated by inhibitory receptors that bind self-MHC class I molecules. The absence of MHC class I expression causes lysis of cells, as described by the 'missing-self' hypothesis.
• Some aspects of NK-cell biology cannot be explained by the regulation of self-tolerance through MHC class I molecules alone, implying the existence of non-MHC-binding inhibitory receptors.
• 2B4 is a prototypical MHC-independent inhibitory receptor. It inhibits NK-cell responses to CD48-expressing cells in mice, as well as in the absence of SAP (signalling lymphocytic activation molecule (SLAM)-associated protein) in humans. This inhibition protects against NK-cell autoreactivity.
• Carcinoembryonic-antigen-related cell-adhesion molecule 1 (CEACAM1) ensures NK-cell tolerance in MHC-class-I-deficient humans.
• Several other NK-cell inhibitory receptors recognize diverse ligands that are markers of 'self'. These receptors include some NK-cell receptor protein 1 (NKR-P1)-family members, sialic-acid-binding immunoglobulin-like lectins (SIGLECs) and glycoprotein 49 B1 (gp49B1).
• Non-MHC-binding inhibitory receptors regulate NK-cell responses in disease states, including infection, cancer and autoimmunity. These receptors might provide new targets for improving NK-cell responses, possibly leading to better treatments for such diseases.

About the authors: Author biographies

Vinay Kumar is the Alice Hogge and Arthur A. Baer Professor, as well as the Chairman, of the Department of Pathology at the University of Chicago (Chicago, Illinois). In the early 1970s, working together with Michael Bennett, he predicted the existence of a non-T-cell, non-B-cell subset of lymphocytes responsible for genetic resistance to the development of certain leukaemias and resistance to engraftment of allogeneic bone marrow in mice. Later, these cells became known as natural killer cells. His research group has delineated the crucial role of bone-marrow stroma for the differentiation of natural killer cells. They have also discovered several natural-killer-cell receptors and identified their functions in vitro and in resistance to engraftment of allogeneic bone-marrow transplants. Vinay Kumar is a past president of the American Society for Investigative Pathology and lead author of the two most widely used textbooks of pathology, Robbins and Cotran's Pathologic Basis of Disease and Robbins Basic Pathology.

Megan McNerney is an M.D. Ph.D. student in the National Institutes of Health Medical Scientist Training Program at the University of Chicago Pritzker School of Medicine. Working with Vinay Kumar, she has characterized the 2B4- and CD48-mediated regulation of mouse natural-killer-cell responses to tumours and allogeneic bone-marrow transplants. She is a recipient of the Zollie and Elaine Frank Family Fellowship for medical research.

May 2005 Vol 5 No 5; Nature Reviews Immunology 5, 363-374 (2005); doi:10.1038/nri1603

Thanks to Co-Cure.org (Mon, 23 May 2005) and Maggie Wallace (zen38947@ZEN.CO.UK).

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