Foxp3+ Tregs undergo memory-loss following inflammation

Adaptive immune system is characterized by its ability to recall prior antigen encounter and to mount stronger and swifter response for the second time. This is what typically happens to conventional T cells. But what about regulatory T cells (Tregs)? Do Tregs also display enhanced recall response when encountering [antigen] for the second time?

The answer is NO according to new study from Rudensky's lab published this week in journal Cell. It appears that while phenotypically and gene-expression wise Tregs do resemble conventional memory T cells, nonetheless Tregs do not undergo enhanced recall response when going through the second time encounter.  

To test this hypothesis, the authors subjected Tregs to inflammatory environment and tracked their behavior. First, they found that phenotypically Tregs returned to "resting" state within 60 days following activation and resolution of inflammation. 

Gene expression analysis confirmed Tregs tested prior to inflammation (resting Tregs) or following inflammation (memory Tregs) resembled each other, while Tregs going through inflammatory process (activated Tregs) had a distinct gene profile. 

    

Functionally too resting Tregs and memory Tregs showed similar potential to inhibit hyper-proliferation of naive T cells when co-transferred into T cell-deficient host.

However, unlike conventional memory CD4 T cells, memory Tregs did not undergo more robust recall response when subjected to inflammation + undefined antigen for the second time.

Finally, the authors observed that Tregs displayed common gene profile with conventional memory CD4 T cells that differentiate them from naive T cells.

In summary, this study suggests two things: first, Tregs do not acquire secondary enhanced recall response capability [at least when exposed to inflammation and undefined antigen] and second, Tregs and conventional memory CD4 T cells share similar gene expression profile.

David Usharauli 

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

This week Immunity published study claiming NK cell response to melanocyte-targeting hapten, monobenzone, display adaptive-like behavior with memory component.

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