Lewis Lanier Discusses "Unlicensed" Natural Killer Cells

Fast Breaking Papers Commentary, February 2011

Lewis Lanier

Article: 'Unlicensed' natural killer cells dominate the response to cytomegalovirus infection


Authors: Orr, MT;Murphy, WJ;Lanier, LL
Journal: NAT IMMUNOL
Volume: 11, Issue: 4, Page: 321-U29, Year: APR 2010
* Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA.
* Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA.
(Addresses have been truncated)

Lewis Lanier talks with ScienceWatch.com and answers a few questions about this month's Fast Breaking Paper paper in the field of Immunology.


SW: Why do you think your paper is highly cited? Does it describe a new discovery, methodology, or synthesis of knowledge? Would you summarize the significance of your paper in layman's terms?

Natural killer cells (NK cells) are a component of the immune system important for controlling infections and cancers. One of the great, unresolved issues surrounding NK cells is how they recognize and kill infected cells and tumor cells while sparing normal, healthy cells.

In recent years several high-profile papers have proposed that only a subset of NK cells that express inhibitory receptors recognizing polymorphic major histocompatibility class I proteins that are present in the host become fully mature and functional, a process referred to as "licensing." In the fully mature, functional NK cells these same inhibitory receptors suppress NK cell activation when they encounter cells expressing the relevant MHC class I ligand. This hypothesis is very attractive because it neatly explains why NK cells do not cause autoimmunity.

The earlier studies supporting the "licensing" hypothesis, however, were largely based on experiments involving the in vitro stimulation of NK cells in plastic dishes, whereas our recent studies described in this article Mark Orr, a senior postdoctoral fellow in our lab, tested this hypothesis using infection of mice with a natural mouse pathogen for which NK cells are critical for host defense.

"Understanding how NK cells function might have important implications in the emerging field of stem cell transplantation. ...as the stem cell therapies become a clinical reality—NK cells best not be forgotten."

When he examined which NK cell subsets are important for controlling cytomegalovirus infection in mice, he discovered that the subset of "unlicensed" NK cells—predicted to be least functional (those lacking the relevant inhibitory receptors for self-MHC class I)—were critical for controlling infection, whereas the subset predicted to be most functional (those expressing the relevant inhibitory receptors and thus "licensed") contributed little to control of the infection. Thus, our findings challenged the hypothesis that only "licensed" NK cells are useful, and further demonstrated that inhibitory receptors indeed dampen the ability of NK cells to fully respond.

SW: How did you become involved in this research, and how would you describe the particular challenges, setbacks, and successes that you've encountered along the way?

My fascination with NK cells began when my good friend and colleague Joe Phillips (my first postdoctoral fellow) generated one of the first monoclonal antibodies against what is now designated CD16—the first definitive marker used to identify and purify human NK cells. In the early '80s, many immunologists didn't believe that NK cells even existed—dismissing "NK activity" as an artifact or promiscuous killing by T cells or macrophages.

Since that time, our lab and others have confirmed their existence as a distinct third lineage of lymphocytes and discovered many of the important features of NK cells. In particular, we have focused on discovering the mechanisms by which NK cells are activated to respond to appropriate targets. Two of our other most recent exciting findings are: (1) understanding how NK cell specifically recognize and eliminate particular viral infections in mice, and (2) discovering that NK cells are able to "remember" an infection and respond more vigorously when that pathogen is re-encountered.

This latter property was previously thought to be an exclusive feature of adaptive immune cells, T and B cells. This suggests that it might be possible to design vaccines that specifically induce "memory" NK cells to control certain infections. As with the studies presented in this article, the notion of "memory" NK cells challenges long-accepted dogma and was not readily accepted when we initially presented the concept, although evidence is mounting to support this proposition.

Another major challenge has been extending our discoveries in mice to humans. Although the effector molecules (e.g., cytokines and lytic proteins) and the signaling pathways are highly conserved in both species, the inhibitory and activating receptors have diversified extensively– presumably in response to the rapid evolution of the MHC genes in these species and the species-specific selective pressures imposed by pathogens. Thus, many of the "rules" that we discover in mice must be validated with human NK cells.

SW: Where do you see your research leading in the future?

Our results described in this article challenge the prevailing hypothesis as to why NK cells do not cause autoimmunity. Thus, how NK cells lacking inhibitory receptors for their own MHC achieve tolerance to self is still an open question that we are actively pursuing.

Additionally, we are interested in extending these findings to humans. By studying the NK cell responses in human patients during viral infection using the latest technologies we hope to determine whether the rules governing NK cell development and education in mice are also relevant to humans.

Moreover, we are working with other groups to determine which NK cell subsets are important for controlling cancers and preventing the re-emergence of latent infections such as human cytomegalovirus.

SW: Do you foresee any social or political implications for your research?

Understanding how NK cells function might have important implications in the emerging field of stem cell transplantation. Prior studies have clearly shown that NK cells can reject hematopoietic ("bone marrow") stem cells that are "foreign" (allogeneic), and likely will also attack stem cells from other tissues if they are not identified as "self." Therefore, as the stem cell therapies become a clinical reality—NK cells best not be forgotten.End

Lewis Lanier, Ph.D.
American Cancer Society Research Professor
Professor and Chair, Department of Microbiology & Immunology
Professor, Cancer Research Institute
University of California, San Francisco
San Francisco, CA, USA

KEYWORDS: NATURAL KILLER CELLS, CYTOMEGALOVIRUS INFECTION, MHC CLASS I, COMPLEX CLASS I, DEFICIENT HEMATOPOIETIC CELLS, INHIBITORY RECEPTORS, MURINE CYTOMEGALOVIRUS, TYROSINE PHOSPHATASE, ACTIVATION RECEPTOR, INNATE RESISTANCE, SELF-TOLERANCE, MISSING SELF.

 
 

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