Simon Grassmann 草人

Stepwise epigenetic signal integration drives adaptive programming of cytotoxic lymphocytes Adaptive programming in lymphocytes during infection depends on when—not just whether—they sense antigen and proinflammatory cytokines such as IL-12. Grassmann et al. reveal that AP-1/STAT4 cooperation links signal timing to lymphocyte fate, tuning CD8+ T cell responses and driving the decision between innate versus adaptive programs in NK cells.

Online now: Stepwise epigenetic signal integration drives adaptive programming of cytotoxic lymphocytes

I want to thank Endi (co-first) and Kimray from the lab who were instrumental, of course my PI Joe @josephsunlab.bsky.social and editor Kavitha @kavithascranton.bsky.social who was incredibly helpful as always :) If you have questions or need help (especially with CUT&RUNs), reach out!

Mechanistically, strong antigen stimulation leads to increased AP-1 factor activity and STAT4 relocation, just like in NK cells. Together, our data suggests that IL-12/STAT4 has a context dependent role for cytotoxic lymphocytes: and the timing and strength of preceding antigen is key!

However, we found that for T cells the mechanism was conserved in a different way: IL-12 signaling depended on antigen strength. In T cells with a strong TCR (from our paper Straub et al. 2023), IL-12 signaling boosted CD8+ T cell memory. But in "weak" T cells the opposite was the case.

Last, we wanted to know if this mechanism is also present in the adaptive counterpart of NK cells - CD8+ T cells. CD8+ T cells do not express IL-12 receptor before antigen stimulation - probably for good reason, since we don't want them to differentiate into terminal cells unless there is antigen.

Together, this suggested to us that timing matters a lot for adaptive NK cell responses: If an NK cell receives early antigen signaling, IL-12 boosts an adaptive fate. But without this early antigen signal, the NK cells are driven into a terminal effector fate, and cannot proliferate.

We used to think that NK cells in general love to receive IL-12 signaling and that IL-12 boosts proliferation via STAT4 in all NK cells. But we found that IL-12 in fact shuts down proliferation - unless the NK cell received antigen signaling first.

Mechanistically, this was dependent on AP-1 factors, which are activated after antigen signaling and lead to chromatin opening. Inhibiting AP-1 prevented the opening of chromatin and subsequent relocalization of STAT4. Next, we wanted to know if this has any effect on the NK cell fate..

...After antigen signaling changed chromatin accessibility, induced STAT transcription factors were relocated. But this was not the same for all: IL-12 dependent STAT4 showed the clearest change in genomic binding. This meant that NK cells receiving this early antigen signal sensed IL-12 different.

These early antigen primed NK cells mounted far better adaptive responses than NK cells which had not received early antigen signaling. We thought that this may affect how cytokine signals are integrated later. Indeed, we found that antigen signaling changes how the genome is "packaged"...

We used to think during MCMV infection that NK cells are first recruited to infection sites via cytokines and then can recognize antigen. My previous paper put that into question (Flommersfeld et al. 2021), and indeed we found that a portion of NK cells actually FIRST sees antigen and then cytokines

Stepwise epigenetic signal integration drives adaptive programming of cytotoxic lymphocytes Lymphocyte differentiation during infection depends on the integration of antigen and cytokine signals, yet how the timing and sequence of these cues …

Excited to share my paper published today in @cp-immunity.bsky.social! We find that when CTLs integrate antigen and cytokine signaling, the timing of these cues matters - shedding light on an old question: Why do NK cells sometimes behave like CD8+ T cells?
www.sciencedirect.com/science/arti...

Neoliberalism in academia—What we can learn from physiology Neoliberalism has transformed academia by centering competition. Competition for high-impact papers and grants is supposed to “optimize” science. Howe…

I didn't expect to be so sad learning that my favorite philosopher, Alasdair MacIntyre, has passed 💔. I hope I can explore lessons from his philosophy for STEM research more in the future, I made a first attempt in this book chapter:

sciencedirect.com/science/arti...

GM-CSF–mediated epithelial-immune cell cross-talk orchestrates pulmonary immunity to Aspergillus fumigatus During mold infection, epithelial-derived GM-CSF licenses neutrophil killing of fungal cells, leading to improved survival.

So happy to see this story come together. Check it out! Kathleen Mills and many collaborators - GM-CSF–mediated epithelial-immune cell cross-talk orchestrates pulmonary immunity to Aspergillus fumigatus | Science Immunology www.science.org/doi/10.1126/...

Traveled to DC today for the Stand Up for Science rally ❤️🔬
We need public funding of science, no cuts!

Splenic TNF-α signaling potentiates the innate-to-adaptive transition of antiviral NK cells NK cells possess innate and adaptive features, but unlike T and B cells, NK cells are not thought to require priming in lymphoid organs. Mujal et al. demonstrate that the spleen supports enhanced expa...

Congratulations to Dr. Adriana Mujal on this @cp-immunity.bsky.social study demonstrating a new role for an age old cytokine! www.cell.com/immunity/ful...

Huge congratulations to @timorckert.bsky.social on receiving the Pettenkofer Prize for our work on human NK cell memory and clonality! A heartfelt thank you to Oliver Keppler and the Pettenkofer-Stiftung for the warm welcome and the wonderful ceremony!

Not sure who can access this outside US universities.. 😬 will try to write articles about the topic soon

Neoliberalism in academia—What we can learn from physiology Neoliberalism has transformed academia by centering competition. Competition for high-impact papers and grants is supposed to “optimize” science. Howe…

I made an excursion into the Humboldt vs. neoliberal university model, some (left) Alasdair MacIntyre takes on virtues in academia and ideas about what to change and how. 😉 Check out my chapter about neoliberalism in academia in this new book: www.sciencedirect.com/science/arti...

You should follow my amazing mentor joe 😊 we have a lot cooking in the lab about to go out, if you are interested in NK cells (and a little CD8 and even B cells 😂) give a follow

hello to everyone on bluesky!

Immunologists (especially if interested in NK cells) should follow @labwaggoner.bsky.social, on twitter the best way to not miss papers 😅 stephen you should ask @rodrahimi.bsky.social to be added to an “immunology starter pack”

This is amazing 😊 could you add me too?

Early antigen receptor signaling in natural killer cells alters STAT4-dependent fate decisions via epigenetic remodeling Natural Killer (NK) cells are innate cytotoxic lymphocytes that possess features of adaptive immunity, including antigen specificity and clonal expansion. NK cells rapidly respond to cytokines release...

Now I study NK cell signaling, in particular antigen and cytokine signaling via STATs. I put something on BioRxiv, but it changed a lot, when I resubmit I will adapt it. Hit me up if you need help with STAT CUT&RUNs, I have established them all (but STAT6 😅)

www.biorxiv.org/content/10.1...

Fate mapping of single NK cells identifies a type 1 innate lymphoid-like lineage that bridges innate and adaptive recognition of viral infection Adaptive-like responses to MCMV are thought to originate from circulating conventional NK cells. Here, Flommersfeld et al. use single-cell fate mapping to show that a separate lineage of spleen-reside...

ILC1-like NK cells as separate lineage:

www.cell.com/immunity/ful...

NK cells first single-cell transfer:
www.cell.com/immunity/ful...

Early emergence of T central memory precursors programs clonal dominance during chronic viral infection - Nature Immunology T cell memory formation is often described as occurring during the chronic phases of infection. Buchholz and colleagues use the phenomenon of ‘memory inflation’ following cytomegalovirus infection to ...

To populate my Bluesky and people know what I do: I am an MD turned immunology "basic" researcher. In the past I did adoptive T cell therapy and then fate mapping in the Buchholz lab in Munich:
CD8+ T cells in MCMV:
www.nature.com/articles/s41...