Thrilled to make the cover of @natimmunol.nature.com this month.

A version of this warhol-inspired image has been in my head almost since we first conceived this Tfh diversity project (many, many years ago) @wehi-research.bsky.social

Further, we identified new cell surface markers to explore these phenotypes across lymphoid tissues and blood with @katherinekedz.bsky.social and with @jenjuno.viralvaxlab.com in an antigen-specific manner, using longitudinal infected or vaccine cohorts.

Next, with Vanessa Bryant (no 🦋), we performed CITE-seq on human tonsil Tfh scRNAseq. This showed that our mouse signatures overlayed with distinct human Tfh clusters.

We found these cytokines act as levers of Tfh phenotypes, beyond Th1-Tfh bifurcation. Highlighting separate transcriptional modules to instruct Tfh cell identity and functional branching. The latter being instructed by cytokines and overlayed by lineage-defining factors to instruct B cell responses.

We next established Tfh-pathogen specific signatures which indicated distinct transcriptional programs, functional potential and highlighted unique cytokine signaling profiles.

This suggested cytokine pathways are a stronger driver of specific heterogeneous Tfh cell phenotypes than pathogen class.

We then performed bulk RNAseq to profile IL21+, and IL21- Tfh cells, T follicular regulatory cells, and T effector cells from each infection.

This allowed us to establish a core Tfh signature that is conserved regardless of pathogen type.

First, we established that each infection established distinct Tfh populations and, with @kimljacobson.bsky.social, tailor distinct B cell responses.

Here, we expand this to investigate how distinct programing is established during diverse challenges, comparing viral, helminth, and bacterial infections.

We hypothesized that pathogen-specific cues result in functionally distinct Tfh phenotypes with the capacity to tailor B cell responses.

CD4+ T follicular helper (Tfh) cells display remarkable functional flexibility, directing B cell responses during vaccination and all pathogen classes and being implicated during inflammatory and antibody-mediated diseases.

Check out the Tfh “circle of influence” from @profshanecrotty.bsky.social

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.

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.

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.

Further, we tracked the plasticity of these two cell states, with antigen availability dictating the transition between CD61+ Tpex and CD55+ Tscm cell states.

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.

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.

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.

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.

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.

Please enjoy the 2024 edition of our #AwkwardLabPhoto
Feel incredibly proud and privileged to work with this crew @wehi-research.bsky.social

Credits:
Creative vision and execution: @benjbroom.bsky.social
Wardrobe: @brigetteduckworth.bsky.social
Best pose (always): @raymondqin.bsky.social