groomlab.bsky.social
Immunologist @WEHI_research. Passionate about inclusive conversations and diversity, both in and outside the Immune system. She/her
36 posts
1,019 followers
697 following
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Congratulations Doug and team
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Lovely work Isaak. Good to see you here.
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Surely we are already there
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This journey was over 2.5 since initial submission 😭
led by @benjbroom.bsky.social with support from the whole lab, @chinweetan.bsky.social, WEHI’s Dynamic Imaging Facility, and Norbert and Colin's teams.
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⭐️ Our work demonstrate that the formation of effector cells is not needed to obtain potent memory T cell responses.
⭐️ Thus our study suggests a new approach to vaccine design to direct stem cell-like memory CD8+ T cell formation and function.
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⭐️ Interplay of type I and II IFNs modify chemokine abundance to position CD8+ T cells within the lymph node. ⭐️This has implications for patients with LOF mutations in IFN-I signaling or auto-IFN-I antibodies.
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⭐️ Our study aligns with others (Utzschneider, Ahmed, Zehn) unifying stem-like cells in acute, chronic infections and cancer
⭐️ Suggesting in chronicity the transition to memory is "interrupted"
⭐️ Importantly we reveal markers that allow these states to be tracked in vaccine/immunotherapy responses
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Combined:
⭐️ CD8+ T cells primed in the absence of IFN-I signaling transition from Tpex to Tscm cells.
⭐️ These are plastic cellular states, with antigen availability dictating the transition between the two.
⭐️ We propose this natural transition promotes development of potent CD8+ memory formation.
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With help from Norbert Pardi @upenn.edu and Colin Pouton @monashuniversity.bsky.social we applied this knowledge to mRNA-LNP vaccination to demonstrate that IFN-I blockade provided protective benefit against subsequent chronic viral infection.
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We demonstrated a counterintuitive increase in IFNg which controlled chemokine abundance and cell location. Whenever we observed cell retention within the paracortex, it was associated with increased stem-like CD8+ T cell formation.
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We investigated how CXCR3 chemokines guide CD8+ T cell location are regulated.
To our surprise, they were increased when IFN-I signaling was inhibited. Yet, CD8+ T cells were retained in the lymph node paracortex due to receptor desensitization.
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Further, we tracked the plasticity of these two cell states, with antigen availability dictating the transition between CD61+ Tpex and CD55+ Tscm cell states.
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Overlaying scRNAseq with Totalseq, we could not only define the transcriptional Tpex and Tscm cell signatures, but cell surface markers that tracked conversion between these transient populations.
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We looked at this differentiation in detail to show that at day 8 post infection, IFN-I blocked stem-like cells appear similar to Tpex cells seen in chronic infection. After viral clearance, the population resemble Tscm, the transition associated with decreased inhibitory receptor expression.
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Wait… doesn’t this just induce chronicity and exhaustion (as demonstrated by the Brooks lab and others)?
The key here is early and transient IFN-I blockade. While delayed, we see total viral clearance with stem-like CD8+ T cell accumulation being distinct from that seen in chronic infection.
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We used early, transient blocking of type I interferon (IFN-I) to promote TCF-1+ stem-like CD8+ T cells in the absence of effector CD8+ T cells during acute LCMV infection.
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Previously we identified that the lymph node paracortex provided a spatial niche which promotes Tscm cell formation. Here, we proposed this niche protects Tscm cells way from inflammation at the lymph node periphery.
www.nature.com/articles/s41...
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TCF-1+ stem-like CD8+ T cells encompass two populations with therapeutic potential:
1. Tscm cells – seen in vaccine and acute infection
2. Tpex cells – seen in chronic infection and cancer
But their developmental relationship and how to individually define or promote them is lacking.
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thanks Lucie
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I pride myself on the thoroughness of my kitchen lab book, but this is next level
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Mission Accomplished!
Although I didnt predict the "hands on Jo" (otherwise know as LZ GC @labphan.bsky.social) would be the one chosen
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honestly, i just turn up and go with it 😂 very fun photo shoot.
hope you get a great break too Doug.
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(had to repost with updated tags)
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😂 I hadnt seen it, but now I can't unsee
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Can we tempt you Adrian?
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Yes please! When do we start subsetting subsets of starter packs?
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its like a breath of fresh (science filled) air 🙌
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Hey Tri, Can you add me?
See you next week!
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Hey Rod, I've just migrated here. Please add me to an #immunology pack.
Cheers, Jo