Highly functional and prolonged germinal center T follicular helper cell responses are associated with enhanced neutralizing antibody development

Ester Marina-Zárate; Henry J Sutton; Paul G Lopez; Tasha K Altheide; Michael Bick; Iszac Burton; Elana Ben-Akiva; Katarzyna Kaczmarek Michaels; Kesha Hyacinth; Brandon S Healy; Deuk Lim; Lars Hangartner; Dennis R Burton; Diane G Carnathan; Guido Silvestri; William R Schief; Darrell J Irvine; Shane Crotty

doi:10.1016/j.immuni.2025.10.008

Highly functional and prolonged germinal center T follicular helper cell responses are associated with enhanced neutralizing antibody development

Immunity. 2025 Nov 7:S1074-7613(25)00462-5. doi: 10.1016/j.immuni.2025.10.008. Online ahead of print.

Authors

Ester Marina-Zárate¹, Henry J Sutton¹, Paul G Lopez¹, Tasha K Altheide¹, Michael Bick², Iszac Burton², Elana Ben-Akiva³, Katarzyna Kaczmarek Michaels⁴, Kesha Hyacinth⁵, Brandon S Healy⁵, Deuk Lim⁵, Lars Hangartner², Dennis R Burton⁶, Diane G Carnathan⁷, Guido Silvestri⁷, William R Schief², Darrell J Irvine⁸, Shane Crotty⁹

Affiliations

¹ Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, San Diego, CA, USA; Consortium for HIV Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, San Diego, CA, USA.
² Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, San Diego, CA, USA; Consortium for HIV Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, San Diego, CA, USA.
³ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Consortium for HIV Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, San Diego, CA, USA.
⁵ Emory National Primate Research Center and Emory Vaccine Center, Atlanta, GA, USA.
⁶ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, San Diego, CA, USA; Consortium for HIV Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, San Diego, CA, USA; IAVI Neutralizing Antibody Center (NAC), The Scripps Research Institute, La Jolla, San Diego, CA, USA.
⁷ Consortium for HIV Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, San Diego, CA, USA; Emory National Primate Research Center and Emory Vaccine Center, Atlanta, GA, USA.
⁸ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, San Diego, CA, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Consortium for HIV Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, San Diego, CA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
⁹ Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, San Diego, CA, USA; Consortium for HIV Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, San Diego, CA, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, San Diego, CA, USA. Electronic address: shane@lji.org.

PMID: 41205611
DOI: 10.1016/j.immuni.2025.10.008

Abstract

Durability of T follicular helper (Tfh) cell responses is pivotal for generating high affinity antibodies. We characterized Tfh cell responses to HIV Env immunization longitudinally in non-human primates, analyzing >500,000 CD4⁺ T cells from 192 lymph node (LN) samples collected over 60 weeks, including >36,000 vaccine-specific Tfh cells. An escalating-dose priming regimen elicited higher and more sustained Tfh cell responses in LNs, compared with conventional bolus immunization. Multiple vaccine-specific germinal center (GC)-Tfh subpopulations, including interleukin (IL)4^hi and IL21^hi GC-Tfh cells, were continually present. Antigen-specific Tfh clones persisted within GCs for over 6 months, maintaining stable gene expression profiles and showing no signs of exhaustion. Vaccine-specific Tfh proliferation signatures were detectable for 27+ weeks after priming. Tfh subpopulations correlated with HIV Env-specific antibody and neutralization titers. Additionally, substantial Tfh clonal migration occurred between LNs. Thus, complex populations of GC-Tfh can enhance antibody responses and survive for 48 weeks in GC responses without new antigen delivery, with implications for immunization regimens.

Keywords: AIDS; CD4 T cells; HIV; T follicular helper cells; Tfh; germinal center; germinal center B cells; neutralizing antibodies; single-cell RNA-seq; vaccines.