Jennifer Juno

This was fantastic work from Mitchell Zheng and Hyon-Xhi Tan working with the @viralvaxlab.bsky.social team, including myself and @wheatleyak.viralvaxlab.com. Thanks to everyone who contributed @thedohertyinst.bsky.social!

We found that TFH differentiation can be tuned by manipulating peptide-MHCII availability on B cells - increasing HA91 presentation on a larger pool of B cells improved stem-HA91 immunogenicity, while decreasing the stem-SMARTA dose selectively reduced TFH numbers without impacting total CD4 priming

Number of epitope-specific CD4 T cells determined by tetramer staining

Number and phenotype of tetramer-specific TFH cells

We used tetramers to confirm that both HA91 and SMARTA peptides were processed and primed similar numbers of CD4 T cells. What differed was their TFH differentiation - HA91-specific T cells failed to develop into a CD90low GC TFH population. As a result, no stem-specific GC formed.

Design and primary immunogenicity of stem-peptide antigens

We next engineered variants of our stem antigen ‘tagged’ with one of these peptides or a well known control epitope – OTII or SMARTA. Some of the peptides were able to rescue the immunogenicity of the stem protein (like HA523 and GP61). Surprisingly, though, the dominant HA91 peptide had no impact.

Map of immunogenic peptides in influenza HA

But what about recombinant protein immunogens? To what extent can individual CD4 epitopes rescue or tune immunogenicity? We started by mapping the CD4 epitopes in PR8 HA, and found a highly dominant peptide (HA91) as well as three subdominant peptides.

Proliferation of ferritin-specific CD4 T cells following 3 doses of stem-ferritin nanoparticle vaccination

It turns out that after repeated boosting, we could find extremely subdominant ferritin-specific CD4 cells (but nothing for stem!) - meaning that these rare responses can support a GC reaction when the antigen is arrayed on a nanoparticle

Immunogenicity of stem versus stem-ferritin nanoparticles in BL/6 mice

So how can we make stem more immunogenic? Up first: stem-ferritin nanoparticles, which elicit a strong IgG response after one immunisation in the mice. This was a bit of a mystery to us, since neither the stem protein nor ferritin nanoparticle contain detectible CD4 epitopes in BL/6 mice.

We focused on the influenza HA stem antigen as an example of a small vaccine immunogen with limited CD4 help. In fact, the stem protein has no CD4 epitopes in BL/6 mice at all, so it serves as a model of a ‘help-less’ immunogen that doesn't elicit a primary antibody response.

TL;DR: Immunodominant epitopes aren't always helpful - some polyclonal T cell populations are poorly recruited into the GC, even if they dominate the CD4 repertoire. Conversely, rare and subdominant CD4s can drive a GC if antigen is presented on a nanoparticle (likely enhancing BCR signalling)

Immunodominance is a poor predictor of vaccine-induced T follicular helper cell quality Our findings emphasise the importance of CD4+ T cell help for programming robust and durable humoural immunity, and provide crucial insights to guide the rational incorporation of favourable T cell ep...

🎉 Our new study of CD4 TFH quality is now online @ebiomedicine.bsky.social! We know that TFH are critical for germinal centres and antibody production, but want to understand whether all CD4 responses can be equally helpful to B cells.

www.thelancet.com/journals/ebi...

I am always so impressed by @marioskoutsakos.viralvaxlab.com’s elegant work on influenza B virus vaccines. Congratulations, Marios, on your Early Career Researcher Award! #19vaccinecongress

Garvan Faculty Member - Sydney (LGA), New South Wales (AU) job with The Garvan Institute | 12841341 The Garvan Institute invites applicants for Faculty-level positions in the Immune Biotherapies and Precision Immunology Programs.

The Precision Immunology and Immune Biotherapies Programs at the Garvan Institute are looking for new Faculty members. Come join us and work with amazing scientists in an amazing place @labphan.bsky.social @garvaninstitute.bsky.social
www.nature.com/naturecareer...

No evidence of immune exhaustion after repeated SARS-CoV-2 vaccination in vulnerable and healthy populations Nature Communications - Repeated vaccination is needed to maintain high levels of SARS-CoV-2 immunity in vulnerable populations, but there is concern that it could lead to immune exhaustion. Here,...

Publication alert: "No evidence of immune exhaustion after repeated SARS-CoV-2 vaccination in vulnerable and healthy populations" ‪@natcomms.nature.com‬ The backstory is particularly interesting-it's a tale of the conflicting needs of scientists & decision makers in times of disinformation ....1/n

Excited to have our latest research published in @jem.org this week and also highlighted by @natrevimmunol.nature.com
@wehi-research.bsky.social @benjbroom.bsky.social

Fantastic work from @labphan.bsky.social and @mlmunier.bsky.social combining mouse models and clinical studies to understand B cell recall following booster vaccination. Check out the paper and thread below! ⤵️

Happy to report that Mitchell's paper on CD4 T cells and AIM assays is now available online at Science Advances!

www.science.org/doi/10.1126/...

Thanks to all our collaborators in @viralvaxlab.bsky.social and @thedohertyinst.bsky.social, including @assocprofashhaque.bsky.social lab

Check out the latest from @viralvaxlab.bsky.social postdoc Wen Shi Lee, developing monoclonal antibodies that neutralise the NL63 coronavirus!

Great new story exploring how B cells can recognise glycans (and still get T cell help!) from @precisionvaxlab.bsky.social and team!

What do you need them for, Julie? We might have other lines that would work for your experiments.

Multi-Dose Vaccines Administered in the Same Site Boost Immune Response  - AAI News New research suggests that receiving multiple doses of a vaccine in the same limb leads to faster antibody development.

New research in @jimmunol.bsky.social from @jenjuno.viralvaxlab.com and Dr. Hyon-Xhi Tan suggests that receiving multiple doses of a vaccine in the same limb leads to faster antibody development. Learn more: news.aai.org/2025/03/10/m.... #medsky #immunosky #idsky

Check out the latest work from @viralvaxlab.bsky.social, now online in @jimmunol.bsky.social!

Should you get the COVID mRNA and flu vaccines in the same or opposite arms?

Randomised trial by Lee, Selva, et al. suggests it is preferable to administer the vaccines at different sites. buff.ly/3D4gX95

Unfortunately, Melbourne isn't going to be quite as seamless of an experience...

If any American immunologists want to write an op-ed for @immunolcellbiol.bsky.social on the impact of the new executive orders, please contact me

Research Officer Job Title Research Officer Job Description An excellent opportunity is available for a Research Officer to join the Groom Laboratory in the Immunology Division at Australia’s pre-eminent biomedical re...

Kicking off the new year searching for a postdoc to join our team @wehi-research.bsky.social
Apply now and spread the word

Thanks Jo!

Thanks Danika!

9/9 Thanks to all our collaborators who helped out with the study, and congrats to Mitchell, who persevered through a lot of possible activation marker combinations!

8/9 In short, we suggest in vitro stimulation activates ag-specific T cells, which secrete cytokines and activate Treg and Th17/22 cells. Without careful phenotyping, all of these cells can get picked up as AIM+, accounting for the Th17-like memory cells found in many virus-specific AIM datasets.

7/9 Mitch sorted tetramer-specific cells, labelled them, and added them back into PBMC before stimulating with the relevant peptide.

He was able to show that ag-specific CD4 cells downregulate CXCR4 while upregulating 4-1BB/CD137, giving us a more accurate way to define antigen specificity.