Unraveling Human T Follicular Helper Cell Development

NIH Pandemic-Era Grants

Pandemic Era Grants

2023

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Principal Investigator: Philip A Mudd
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2023
Award: $581,189
Funding agency: National Institute of Allergy and Infectious Diseases

ABSTRACT
Neutralizing antibodies are critical for protection from infectious diseases. The lymph node (LN) germinal center
(GC) is the site where B cells undergo antibody affinity maturation and develop into long-lived plasma cells – key
events that are required for the development of highly effective neutralizing antibodies following infection or
vaccination. T follicular helper cells (TFH) are the CD4+ T cell subset responsible for providing B cell help during
an ongoing GC. TFH are absolutely required for GC formation and maintenance. By extension, TFH are necessary
to produce effective neutralizing antibodies following antigen exposure. While many aspects of the TFH response
and TFH function have been examined in animal models, human TFH responses in the draining LN have only
recently been explored with the novel application of an established technique: serial ultrasound-guided fine
needle aspiration of draining LN following vaccination. With this technique, we recently demonstrated that the
antigen-specific TFH response to SARS-CoV-2 spike (S) protein mRNA vaccination persists in the GC for more
than 4 months following vaccination and correlates with the presence of S-specific GC B cells. Furthermore, we
have noted substantial LN TFH transcriptional phenotypic changes suggestive of functional maturation over this
prolonged GC time interval using single cell RNA-seq in a small preliminary cohort. In this proposal, we will
expand upon these findings to address our primary hypothesis: human TFH phenotypic maturation occurs over
time in the draining LN following vaccination and these phenotypic changes are associated with changes in TFH
function. To explore this hypothesis, we propose three specific aims: 1) We will first establish that TFH phenotypic
maturation occurs over time in multiple antigen-specific TFH populations that we will define and characterize from
a cohort of fourteen COVID-19 mRNA vaccine recipients using single cell RNA-seq and ex vivo epitope
identification methods. 2) We will determine how these antigen-specific TFH populations change in a tertiary
immune response following COVID-19 mRNA vaccine “boost” and continued serial LN sampling of the same
cohort participants. We will also ascertain if new antigen-specific TFH populations are recruited to the GC during
a recall response. 3) Finally, we will verify that the profound phenotypic changes we observe lead to changes in
the functional capacity of antigen-specific TFH to provide help to B cells using an ex vivo system of sorted human
LN TFH and an in vivo murine adoptive transfer model. By addressing these aims, we will significantly enhance
our understanding of the role that human TFH play in directing GC B cell responses to vaccination.

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