Thursday, June 9, 2016

Do innate NK cells truly show memory-like response to antigens? Monobenzone [hapten] study

The concept itself is quite new and not fully developed  [first report of this kind was published in 2006]. I personally do not see that data presented so far support proposal that NK cells have canonical "adaptive memory". For example, one of the hallmarks of adaptive memory response is that secondary response is stronger and more durable compared to primary response. However, in this new paper both primary and secondary hapten-specific response by NK cells show equal magnitude.

To confirm memory response by NK cells, in my view, the authors should show that (a) NK cell response is antigen-[hapten] specific, (b) it is long-lived and (c) secondary response is stronger. 

There is no doubt that in this paper NK cells show antigen-specific response (condition A) and such response could persist for relatively long term (ranging from few weeks to few months, condition B). However, condition C has not been met. In crucial experiment, the authors transferred NK cells recovered after primary response into naive host and then challenged the host 1 week later. However, for some reason, the authors also applied hapten 1 day after NK cells transfer [and before secondary challenge]. This basically prevented testing of recall response.

Only experiment that the authors performed to show long-lived NK cell memory response was the experiment wherein hapten-primed mice were left to sit around for 4 months and then challenged for the second time. However, in this scenario it is hard to tell whether it is true memory response or hapten simply persisted in mice and kept NK cells in active "effector" phase. In addition, in this experiment, both primary and secondary responses were of equal magnitude.

In summary, so far I have not seen definite results in support of "canonical" NK cell memory.

David Usharauli


  1. Dear David. Thank you for your interest in our work. There is a mechanistic difference between contact hypersensitivity (CHS) responses mediated by adaptive T and B cells, and those mediated by NK cells. This has been previously established by Rouzaire et al. Eur J Immunol (2011): The ear swelling in a T cell-driven CHS responses indeed tends to increase a little bit in magnitude with every elicitation. This is likely caused by the adaptive immune cells, in particular T cells, forming a skin tissue-resident memory population at the elicitation site. CHS ear swelling responses induced by only NK cells, typically show an ear swelling response that is equal in magnitude in every elicitation round. Hence, the monobenzone-induced ear swelling being of equal magnitude every time it is elicited, and monobenzone being a selective NK cell-based CHS response, does not preclude the existence of “memory”.

  2. Thanks for comment. Since my view on memory is "T cell-centric", it is possible that NK cells do have memory response that is qualitatively different from that of T cells [for example, it does not show enhanced response, as you mentioned]. The puzzling aspect of such "equal" response would be that it raises additional questions such as what's point of memory if it is the same as primary response? To explain it, one needs to add additional conditions to justify presence of memory response [kinetics, for example or even requirements for priming, etc].