Modeling NK Cell Receptors To Learn From Aging Immune Systems

Biologics

modeling nk cell receptors biovia offerings
The NKG2D protein, an NK cell receptor. Source: European Bioinformatics Institute.

What’s the mechanism that causes elderly people to have weaker immune systems than the young? This question has driven immunologists mad for the past decade, yet thanks to new research joining a forming hypothesis, they may be closer to the answer than ever before. In a study of natural killer (NK) cell function across age groups, recent research has confirmed that NK cells downregulate inhibitory receptors and upregulate excitatory receptors as we grow from child to adult, and then again as we age from adult to elderly.1 This research links to other research which points to immune experience with fighting infection and changing receptor densities as essential determinants of immune function through aging.2 3 Given the number of factors involved in making a comprehensive picture of an individual’s NK cell complement, researchers will need to bring molecular modeling software to bear on the most common receptor isomorphs to determine how else aging influences the immune system and create effective therapeutics.4

Raising a Killer

As like other immune cells, NK cells are formed via hematopoiesis, and have a panorama of surface receptors.5 Some of these receptors are intended for endogenous antibody ligation, whereas others are intended for interface with other immune cells or with hostiles.6 As noted by the authors of the new research, NK cell receptor repertoires are highly variable from cell to cell under normal conditions.

As the body ages, the proportion of receptors expressed by the NK cell changes. The new paper claims that inhibitory receptors are expressed less, and excitatory receptors are expressed more as a result of normal aging from childhood to adulthood. It’s tempting to speculate that this proportional change is one of the major factors which make healthy adult immune systems more robust than the immune systems of children, and there’s some research indicating that this is the case.7 If that’s the case, it’s also tempting to speculate that the compromised immune systems of the elderly are the result of an opposite action, but as the researchers discovered, this isn’t the case at all.

Importantly, the researchers propose that people experience a breakdown in their NK cell diversity as they age further, which is associated with worse immune outcomes despite increasing upregulation of excitatory receptors. Thus, it seems as though a new piece of the immune system aging hypothesis is the maintenance of diversity to maintain immune function, which is a bit counterintuitive. Based off of the childhood to adulthood transition in NK receptor densities, maintaining diversity—which is to say, maintaining a panorama of inhibitory receptors alongside a population of excitatory receptors—seems like a surefire way to have a weaker immune system. According to the new research, the secret is in the isomorphs.

Biologists understand that not all receptor isomorphs are created equal, and NK cell receptors are no exception. Some isomorphs of receptor elicit a greater response when ligated than others, and having the right mix of isomorphs means that immune responses won’t be too aggressive or too passive. The new research found that the isomorph proportions of excitatory killer-cell immunoglobulin-like (KIR) receptors were the factors that were changing the most as NK cells aged rather than the ratio of excitatory receptors to inhibitory receptors, a major twist in the canon of immune senescence. Understanding isomorphs of the NK cell receptor is about to become more important than ever before.

Thus, aging NK cells maintain the major changes brought on by maturing from child to adult which sacrifice diversity of receptor class in favor of an aggressively excitatory mixture, but have to fight eroding of the diversity of excitatory receptor isomorph as aging progresses. Simply put, aging NK cells have larger proportions of excitatory receptors that don’t provide as much excitation as those more common in healthy adults.

This means that researchers studying immune system aging need to understand the following axes of data before planning an experiment:

  • Influence of genetics on NK cell receptor inhibitory/excitatory balance
  • Influence of genetics on NK cell receptor isomorph distribution
  • Relative excitative or inhibitive ability of each NK cell receptor isomorph
  • Influence of genetics on NK cell receptor balance and isomorph distribution from childhood to adulthood
  • Influence of genetics on NK cell receptor balance and isomorph distribution from adulthood to elderhood
  • Influence of chronic or acute immune challenges during each stage of life on the genetics, balance, isomorph distribution, and isomorph ability magnitude of NK cell receptors

It’s clear that the formerly “simple” field of NK cell immunology has suddenly become a very complicated network of factors.       

Providing Assistance To Veteran NK Cells?

The potential applications of a complete NK cell senescence hypothesis are obvious: understanding how and why all of the variables surrounding NK cell receptors change with age will allow for more effective therapeutics which could be built with elderly immune systems in mind. Biologics that might be too broadly activating to be usable in middle-aged people could be tailored to work perfectly in the receptor environment of the old, giving them a chance at fighting diseases they wouldn’t be able to otherwise. The core barrier separating researchers from designing these therapeutics isn’t experimental, but rather informational.

Designing a biologic which targets a specific receptor isomorph that’s highly represented in a certain population requires powerful modeling software that can accommodate high sensitivity. So far, NK cell researchers have had little need for such fine tools, as they’ve been content to develop broadly applicable biologics which target without respect to receptor isomorph distribution. Now, researchers will be doing themselves a disservice by allowing nature to determine whether their biologic therapy doesn’t have the maximum impact because of optimization for an absent receptor isomorph.

BIOVIA Biologics is the biological modeling and analytics suite that the researchers of the present and future will use to design immune system supporting biologics for use in the elderly. With BIOVIA’s biologics tools, your team can design therapeutics with the patient’s receptor distribution in mind so that there’s no chance of failure. Contact us today to find out how you can use BIOVIA Biologics to jump start the production of NK cell therapeutics for the elderly.

  1. “Age-Related Changes in Natural Killer Cell Repertoires: Impact on NK Cell Function and Immune Surveillance.” April 2016, https://link.springer.com/article/10.1007/s00262-015-1750-0.
  2. “Reciprocal Age Related Change in Natural Killer Cell Receptors For MHC Class I.” July 2005, http://www.sciencedirect.com/science/article/pii/S0047637405000278.
  3. “Variation of Human Natural Killer Cell Phenotypes With Age: Identification of a Unique KLRG1-Negative Subset.” July 2010, http://www.sciencedirect.com/science/article/pii/S0198885910000868.
  4.  “Comparative Analysis of NK Cell Receptor Repertoire in Adults and Very Elderly Subjects With Cytomegalovirus Infection.” March 2017, http://www.sciencedirect.com/science/article/pii/S0198885917300046.
  5. “Preclinical Characterization of 1-7F9, a Novel Human Anti-KIR Receptor Therapeutic Antibody That Augments Natural Killer-Mediated Killing Of Tumor Cells.” September 2009, http://www.bloodjournal.org/content/bloodjournal/114/13/2667.full.pdf?sso-checked=true.
  6. “KIR: Diverse, Rapidly Evolving Receptors of Innate and Adaptive Immunity.” October 2002, https://www.ncbi.nlm.nih.gov/pubmed/11861603.
  7. “Age-Related Changes In Natural Killer Cell Receptors From Childhood Through Old Age.” April 2011, http://www.sciencedirect.com/science/article/pii/S0198885911000176.