Monday, September 19, 2011

Something to squeak about: “Dirty” Wild Mice may be Better Models for Immunological Studies

When we become infected with a virus or develop cancerous cells, our bodily friend group expands as natural killer cells (NK) come to our defense to protect us from these nasty invaders. Like a trained body guard, the NK cells immediately respond to enhance our immune system by defending us against microbes and tumors in our bodies. They have granules in their cytoplasm which host proteins such as perforin and proteases (granzymes) which are released near a pathogen. Upon release, the perforin perforates holes in the cell membrane of the pathogen through which the granzymes and associated molecules can enter to induce apoptosis[o1] .  Interferons and macrophage-derived cytokines activate NK cells to contain viral infections while the adaptive immune response is generating antigen-specific cytotoxic T cells.
Much of what we have learned about immunological processes such as these have stemmed from research on animal models. Mice serve as an important model organism to study molecular mechanisms in immunology.  NK cells from laboratory mice respond poorly to stimuli unless the mice are treated with toll-like receptor (TLR) agonists, cytokines or infection. Previous studies indicate that NK cells are extremely low in lymph nodes (LNs), to lack perforin or granzyme B (Gzmb) and to die prematurely in cytokine absent cultures (Fehniger et al. 2007; Long 2007). This starkly contrasts with NK presence in humans which are profuse in LNs, contain perforin and Gzmb and survive better. Previously these discrepancies were attributed to the fact that the differing species had varying NK cells.  NK cells were believed to be short-lived and innate.  Recent studies, however, suggest that NK cells may be live longer than was previously thought.

A new study found that NK cells in vivo rely on priming of microbial structures by dendritic cells (DCs) in the LNs to function fully. Other studies have found evidence that NK cells might rely on a memory-like mechanism following infection or cytokine interactions. The developments in research provide evidence of priming and memory possibilities that challenge the previously established belief that NK cells are typically innate, non-adaptive lymphocytes.
            In the study conducted by Boysen et. al 2011, Natural killer cells in free-living Mus musculus have a primed phenotype, researchers examined whether NK cells of feral mice exhibited signs of being primed and having memory-like capabilities.  As a result of discrepancies suggesting a microbial imprint on NK, the researchers decided to substitute wild mice captured in their natural habitat (feral), which are exposed more frequently to infectious antigens and thus have a more activated immune response in terms of antibody responses, for the more generally used C57BL/6 mice housed in specific pathogen free (SPF) housing facilities. Researchers collected 10 female and 12 male mice from 5 separate outdoor locations in southeastern Norway and 19 female 12 male SPF mice. They killed the mice using CO2 and analyzed their blood, spleen, mesenteric and peripheral LNs.  They found that NK cell numbers in blood, spleen and mesenteric LNs were comparable between feral and lab mice. However, feral mice exhibited an increase in NK cells in peripheral LNs. LNs are known to be sites for microbial activation and priming of NK cells in other models which suggests priming processes may also occur in wild mice.
The authors also used interleukin 2 (IL-2) or IL-15 to stimulate collected splenocytes and studied the upregulation of activation markers and intrallecular Interferon gamma (INF-y). They found that feral mice but not lab mice acquired a rapid expression of CD25, a marker of activated B cells, suggesting a pre-activation, priming, mechanism in feral mice. A stronger INF- stronger INF-y response upon restimulation was also found. This supports studies which found the presence of primed and memory capable NK cells. 
These findings corroborate recently proposed theories that NK cells rely on a microbial priming phase to transform into fully activated cells. They show that NK cells of feral mice have an activated phenotype and react quickly to cytokine stimulation.This supports the hypothesis that the mice have a primed lineage of NK cells, which fascinatingly and unexpectedly differ from the regularly used C57BL/6 “lab” mice.  The observed augmented NK cell activity in wild mice could support the hypothesis from recent studies that NK suggest cells house imprints of previous microbial interactions and remain for long periods as "memory-like" cells. This data implies that that immunological research in the traditional mouse model under SPF conditions may exclude key information about NK based immune responses, since these important cellular players will not have gone through the microbial priming that would carry out in a mouse or a human's natural environment. Therefore the traditional lab mouse research model might need to be replaced with a feral model that accounts for environmental factors that more accurately represent the immune system of mice and humans (Wiley-Blackwell).

Preben Boysen, Dag M. Eide, Anne K. Storset. Natural killer cells in free-living Mus         musculus have a primed phenotype. Molecular Ecology, 2011; DOI:   10.1111/j.1365-294X.2011.05269.x

Other sources:

Fehniger TA, Cai SF, Cao X et al. (2007) Acquisition of murine NK cell cytotoxicity    requires the translation of a pre-existing pool

Long EO (2007) Ready for prime time: NK cell priming by dendritic cells. Immunity, 26,           385–387.

Wiley-Blackwell (2011, September 8). 'Dirty' wild mice may be more relevant  immunology model. ScienceDaily. Retrieved September 13,

 [o1]Maybe just a couple words explaining apoptosis


  1. Great discovery to make experiments with mice more accurate.

  2. I thought this was really interesting - I wonder if other studies using mice or other common model organisms have similar issues that haven't been addressed. Something to think about! Have feral mice been used in other studies of disease or the immune system besides the NK cell study?