PREreview del NK cells undergo transcriptional and functional reprogramming following Streptococcus pneumoniae infection

Summary

This manuscript from the Universite Paris Cite explores the memory response capability of Natural Killer cells with bacterial infections. The scientists claim that memory responses by adaptive immune cells and even NK cells for viral infections have been heavily studied, but NK cells’ role specifically with bacterial infections is relatively understudied. While there does seem to be other papers exploring this idea of innate memory capability in the last few years (1,2,3), I agree that this paper introduces novel data towards that concept. In the experiment, the researchers intranasally infected female mice with the Streptococcus Pneumoniae bacteria and extracted NK cells of both infected and uninfected mice. Then, they infected the mice again to test for changes in NK cell protection. After conducting single-cell RNA sequencing to compare the NK cells’ activity, they found a significant transcriptional response on the infected group of NK cells through enhanced activation markers, proliferation, and cytotoxicity. Additionally, they were able to purify/isolate NK cells at different times post-infection to study in vitro, which gave them a more comprehensive view of the response. Overall, the genome analysis strongly validates the potential of NK cells to have innate immune memory, but the following concerns should still be addressed:

Major Concerns

·      Though novel RNA activity was well-explored, there weren’t any insights into how the NK cell recognized the bacterial infection in the first place. The paper states that the NK cell receptors that are typically upregulated during viral infections were not upregulated following bacterial exposure, which indicates that they do not play a role in recognizing S. Pneumoniae. The paper never explicitly states what receptors enable infection, which would a strong addition. While this paper focuses on the change in NK cell activity post-infection, I suggest that the paper try to include infection mechanisms as well.

·      This paper identified some of the heterogenous clusters of NK cell populations that are associated with protective benefits from NK memory but didn’t provide a detailed overview of their characteristics. Addition of those details would identify specific features that could lead to memory among NK subpopulations and help further explain their precise role in immunity.

·      I believe the longest duration of NK memory tested was 21 days, so it is important to determine whether NK cells retain these memory-like capabilities for longer-term periods. The papers states that NK cell derived protection may last for at least 12 weeks, but the molecular basis for that requires expansion. I believe the self-citation from the 2023 publication (4) explores this more in depth but is not comprehensive in the molecular mechanisms behind it.

Potential Future Experimental Additions:

·      Adding on to the last point, potentially testing NK cell memory for periods of at least 12 weeks using similar RNA processing and protein analysis could increase certainty about NK memory permanence.

·      All trials are done in mice or in vitro, so the conclusions of this study cannot be translated to human models which restricts immediate clinical relevance.

·      Ideally, more experimentation is done use RNA sequencing and protein analysis with other strains of bacteria to validate NK cell memory beyond S. pneumoniae.

Strengths

·      The usage of Single-Cell RNA Sequencing allows the researchers to profile NK cell transcription activity at a high accuracy and resolution. This allows the paper to look into transcription validation, rather than basic claims on phenotypic information.

·      The study identified distinct, heterogeneous clusters of NK cells which is another point of novelty and supports a more complex model of NK memory rather than simply a uniform population. They were able to explain how NK cells may transition between active and resting phases, which suggests a mechanism in how they stay prepared for new infections.

·      Instead of solely focusing on RNA, the paper explores the phenotypic function associated with those RNA/genotypes which exhibited the genuine relevance of their findings. The proteins that were expressed, and measured through flow cytometry, had important functions for the NK cell.

Overall Thoughts

This is a clear and well-written paper that incorporates justifiable and reliable data to support the idea of innate immune memory capabilities. There are many potential applications including vaccines/infection control and further research into how we can utilize NK cell’s immediate response potential coupled with memory to open new doors in infectious disease/immunology research. With a few added important details, this paper should certainly be published to inspire further research into the possibilities and applications of NK cell memory.

References:

1.     Romee R, Schneider SE, Leong JW, Chase JM, Keppel CR, Sullivan RP, Cooper MA, Fehniger TA. Cytokine activation induces human memory-like NK cells. Blood. 2012 Dec 6;120(24):4751-60. doi: 10.1182/blood-2012-04-419283. Epub 2012 Sep 14. PMID: 22983442; PMCID: PMC3520618.

2.     Guevara Lopez ML, Gebo A, Parodi M, Persano S, Maus-Conn J, Mingari MC, Loiacono F, Orecchia P, Sivori S, Cantoni C, Gentili M, Facchinetti F, Ferracini R, Vallera DA, Felices M, Bertolini G, Pravetoni M, Roz L, Vitale M. CD56^bright cytokine-induced memory-like NK cells and NK-cell engagers synergize against non-small cell lung cancer cancer-stem cells. J Immunother Cancer. 2025 Feb 12;13(2):e010205. doi: 10.1136/jitc-2024-010205. PMID: 39939140; PMCID: PMC11822435.

3.     Marin ND, Becker-Hapak M, Song WM, Alayo QA, Marsala L, Sonnek N, Berrien-Elliott MM, Foster M, Foltz JA, Tran J, Wong P, Cubitt CC, Pence P, Hwang K, Zhou AY, Jacobs MT, Schappe T, Russler-Germain DA, Fields RC, Ciorba MA, Fehniger TA. Memory-like differentiation enhances NK cell responses against colorectal cancer. Oncoimmunology. 2024 May 7;13(1):2348254. doi: 10.1080/2162402X.2024.2348254. PMID: 38737793; PMCID: PMC11086027.

4.     Camarasa TMN, Torné J, Chevalier C, Rasid O, Hamon MA. Streptococcus pneumoniae drives specific and lasting Natural Killer cell memory. PLoS Pathog. 2023 Jul 24;19(7):e1011159. doi: 10.1371/journal.ppat.1011159. PMID: 37486946; PMCID: PMC10399893.

Competing interests

The author declares that they have no competing interests.

Use of Artificial Intelligence (AI)

The author declares that they did not use generative AI to come up with new ideas for their review.