CXCR6⁺ CD127⁻ Tr1 Cells Balance Immunity and Persistence in Plasmodium falciparum Infection

Product:

Inflammation Panel 250

Topic:

Immunology

Disease Area:

Malaria

Sample Type:

Plasma

Topic/Product:

Inflammation Panel 250

Disease Area:

Malaria

Sample Type:

Plasma

Abstract

Plasmodium falciparum (Pf) induces the clonal expansion of antigen-specific type 1 regulatory T (Tr1) cells with a capacity for long-term memory. Tr1 cells comprise nearly 90% of the Pf blood stage antigen-specific CD4+ T cell pool in children. Though, whether Tr1 cells contribute to protection from malaria remains undetermined. To address this critical gap in knowledge, we first performed scRNAseq on gated cell populations to validate CXCR6+ CD127- as new phenotypic markers to enrich for bona-fide Tr1 cells. Importantly, these Tr1 cells potently suppressed the proliferation of other CD4+ T cells in vitro via IL-10 secretion. Among children living in malaria-endemic Uganda, CXCR6+ CD127- Tr1 cells were the dominant responding subset to Pf-infected red blood cell stimulation in vitro. They also rapidly expanded following malaria and expressed IL-10 and IFNg during infection in vivo. Tr1 abundance correlated with plasma concentrations of granzyme A, IFNg, IL-10, and LAG3, suggesting that these cells act systemically. Higher CXCR6+ CD127- Tr1 cell frequencies correlated with a lower probability of symptoms given parasitemia but were also associated with delayed parasite clearance among untreated, asymptomatic children. These data suggest that Tr1 cells help mediate clinical immunity to malaria but may also facilitate parasite persistence through mechanisms of immune regulation.

Authors & Affiliations

Jason Nideffer1,2, Florian Bach1, Steven Strubbe2, Luis Lopez1, Maato Zedi3, Felistas Nankya3, Jessica Briggs4, Kattria van der Ploeg1, Kenneth Musinguzi3, Soyeon Kim1, Aracely Garcia Romero1, Arefin Keya4, Kylie Camanag1, Savannah Lewis1, Muhammad Abdelbasset1, Bing Wang2, Allison Boss2, Evelyn Nansubuga3, Joaniter I Nankabirwa3, Emmanuel Arinaitwe3, Saki Takahashi5, Grant Dorsey4, Bryan Greenhouse4, Isabel Rodriguez-Barraquer4, Moses R Kamya3,6, Rosa Bacchetta2, Isaac Ssewanyana3, Ashraful Haque7, Maria Grazia Roncarolo2*, Prasanna Jagannathan1,8*

Affiliations:

Department of Medicine, Stanford University; Stanford, United States
Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University; Stanford, United States
Infectious Diseases Research Collaboration; Kampala, Uganda
Department of Medicine, Division of HIV, ID, and Global Medicine, University of California San Francisco; San Francisco, United States
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health; Baltimore, Maryland, United States
Department of Medicine, Makerere University; Kampala, Uganda
Department of Microbiology and Immunology, University of Melbourne, at The Peter Doherty Institute for Infection and Immunity; Parkville, Victoria, Australia.
Department of Microbiology and Immunology, Stanford University; Stanford, United States

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.