Our new paper is out on @medrxivpreprint!

How does the immune system need to respond in order to make strong antibody responses to vaccination?

See thread below👇 for a summary of what we found.

@LintermanLab @EdjCarr @BabrahamInst
@CCSMonash @ImmunologyMU
1) In 2 cohorts of UK adults, we studied 53 immune variables before and after seasonal #Influenza vaccination; including antibodies, cytokines, B cells & CD4+ T cells.
Importantly, using tetramers we could track vaccine-specific CD4+ T cells, which expanded beautifully after vax!
2) We found that many of these vaccine-specific CD4+ T cells had differentiated into circulating T follicular helper cells on d7 - a cell type critical for supporting antibody responses (left).

These TET+cTfh cells were a strong predictor of the vaccine-induced IgG (right).
3) We isolated these rare cells and sequenced their T cell receptor repertoire.

These vaccine-reactive cTfh cells derive from a memory T cell pool that is present prior to vaccination (left), and some TCR sequences showed large clonal expansion post vax (right).
4) We found that these TET+ cTfh cells in the blood expressed a similar transcriptome to Tfh cells within lymph node germinal centres (left).

This included down-regulating several cytokine/inflammatory pathways like IL-2 and TNFa (right).
5) Having defined the ideal response in adults, we wanted to find out what changes as we age.

We studied older individuals (left), an age-group that is known to mount impaired antibody respnses to the flu vaccine (right).
6) We found that over 65 year olds dont progress as far along a vaccine trajectory of the immune responses as younger individuals (left).

One key cell type that accounted for this was a reduced follicular helper T cell differentiation in older people (right)
7) What is behind this defect in Tfh cells in ageing?

We show it's not due to loss of T cell receptor repertoire diversity in ageing, as is the current dogma.
Nor due to differences in pre-exisiting immunity

Instead, we found a link to excess extrinsic inflammatory signals.
8) We dug into this inflammation gene signature within vaccine-specific Tfh cells further, and show that it negatively correlated with antibody response to flu vaccine in our cohorts (left), and another from the USA (right).
9) Overall, by tracking vax-specific cells using tetramers we found:
-> Flu vax induces Tfh cells from pre-existing memory.
-> Tfh cells strongly correlate with Abs, and are impaired in ageing.
-> Inflammation was linked to poor Tfh and antibody responses.
10) Thanks to all co-authors, including
@EdjCarr Silvia Innocentin and @LintermanLab @BabrahamInst
@Dr_James_Lee @Cambridge_Uni
Bill Kwok and Eddie James @BRIautoimmune
Martin Zand & Jiong Wang from Uni of Rochester

& particularly @NIHRBioResource for running our cohorts!

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