Post-vaccination expansion of extrafollicular Th10 and regulatory Tfr cells distinguishes strong from weak influenza vaccine responses in older adults

Product:

Inflammation Panel 250

Topic:

Inflammation

Disease Area:

Influenza

Sample Type:

Plasma

Product:

Inflammation Panel 250

Topic:

Inflammation

Disease Area:

Influenza

Sample Type:

Plasma

Abstract

Despite the superior efficacy of high-dose influenza vaccines, over one-third of older adults fail to respond. Yet, the mechanisms underlying this impaired vaccine responsiveness remain poorly understood. Here, we performed longitudinal profiling of older adults (n=60) receiving high-dose influenza vaccination to identify immune programs associated with vaccine responsiveness. Strong responders exhibited a primed baseline immune state characterized by elevated plasma cytokines and chemokines, followed by enhanced IFN-γ responses and coordinated transcriptional and epigenetic activation of cDC2 cells at day 1. By day 7, CD4⁺ T-cell trajectories diverged: strong responders preferentially expanded influenza-specific activated cTfh1 (CXCR5+ CXCR3+ ICOS+ CD38+) and influenza-specific Th10 (CXCR5⁻ CXCR3+ PD1+ IL10⁺) cells, whereas weak responders expanded regulatory cTfr (CXCR5⁺ FOXP3⁺) cells. Th10 expansion correlated with plasmablast and antibody responses and was independently validated in a larger influenza vaccination cohort, including younger adults. Functionally, Th10 cells promoted memory B-cell differentiation into plasmablasts and production of influenza- specific IgGs. TCR analyses revealed minimal clonal overlap between Th10 and cTfh1 cells. Together, these findings identify divergent helper and regulatory CD4⁺ T cell programs associated with vaccine responsiveness and establish Th10 cells as a previously unrecognized component of vaccine-induced humoral immunity.

Authors and Affiliations

Avinash S. Mahajan1,2*, Sathyabaarathi Ravichandran1*, Radu Marches1, Yilmaz Yucehan Yazici1, Sean Nelson3, Teresa Aydillo-Gomez4,5, Kshitija Kshitija1, Amaya Rojo-Fernandez4,5,6, Djamel Nehar-Belaid1, Lisa Kenyon-Pesce7, Daniel Klimes1, Haebeen Jung1,8, Peter Sage9, Virginia Pascual3, Patrick Wilson3, Adolfo García-Sastre4,5,11,12,13,14, Jacques Banchereau1,10‡, George A. Kuchel7‡, Duygu Ucar1,2#‡

1 The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT, USA.
2 Department of Genetics and Genome Sciences, UConn Health, Farmington, CT, USA.
3 Gale and Ira Drukier Institute for Children’s Health and Department of Pediatrics, Weill Cornell Medicine, New York, USA.
4 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, USA
5 Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, USA
6 Department of Health Sciences, University of Burgos, Burgos, Spain
7 UConn Center on Aging, Farmington, CT, USA.
8 Department of Immunology, UConn Health, Farmington, CT, USA.
9 Department of Medicine, Transplantation Research Center, Division of Renal Medicine, Brigham and Women’s Hospital, Boston, MA, USA
10 Immunoledge LLC; Montclair, NJ, USA.
11 Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
12 Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, USA
13 The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
14 The Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, USA

Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition. He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.