PT  - JOURNAL ARTICLE
AU  - Ramin Sedaghat Herati
AU  - Luisa Victoria Silva
AU  - Laura A. Vella
AU  - Alexander Muselman
AU  - Cecile Alanio
AU  - Bertram Bengsch
AU  - Raj K. Kurupati
AU  - Senthil Kannan
AU  - Sasikanth Manne
AU  - Andrew V. Kossenkov
AU  - David H. Canaday
AU  - Susan A. Doyle
AU  - Hildegund C.J. Ertl
AU  - Kenneth E. Schmader
AU  - E. John Wherry
TI  - Vaccine-induced ICOS+CD38+ cTfh are sensitive biosensors of age-related changes in inflammatory pathways
AID  - 10.1101/711911
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 711911
4099  - http://biorxiv.org/content/early/2019/07/24/711911.short
4100  - http://biorxiv.org/content/early/2019/07/24/711911.full
AB  - Humoral immune responses are dysregulated with aging but details remain incompletely understood. In particular, little is known about the effects of aging on T follicular helper (Tfh) CD4 cells, the subset that provides critical help to B cells for effective humoral immunity. We previously demonstrated that influenza vaccination increases a circulating Tfh (cTfh) subset that expresses ICOS and CD38, contains influenza-specific memory cells, and is correlated with antibody responses. To directly study the effects of aging on the cTfh response, we performed transcriptional profiling and cellular analysis before and after influenza vaccination in young and elderly adults. Several key differences in cTfh responses were revealed in the elderly. First, whole blood transcriptional profiling defined cross-validated genesets of youth versus aging and these genesets were, compared to other T cells, preferentially enriched in ICOS+CD38+ cTfh from young and elderly subjects, respectively, following vaccination. Second, vaccine-induced ICOS+CD38+ cTfh from the elderly were enriched for transcriptional signatures of inflammation including TNF-NFkB pathway activation. Indeed, we reveal a paradoxical positive effect of TNF signaling on Tfh providing help to B cells linked to survival circuits that may explain detrimental effects of TNF blockade on vaccine responses. Finally, vaccine-induced ICOS+CD38+ cTfh displayed strong enrichment for signatures of underlying age-associated biological changes. Thus, these data reveal key biological changes in cTfh during aging and also demonstrate the sensitivity of vaccine-induced cTfh to underlying changes in host physiology. This latter observation suggests that vaccine-induced cTfh could function as sensitive biosensors of underlying inflammatory and/or overall immune health.One sentence summary Transcriptional profiling of vaccine-induced circulating T follicular helper cell responding to influenza vaccination reveals age-associated effects on Tfh such as alterations in TNF-NFkB signaling.