T follicular helper 17 (Tfh17) cells are superior for immunological memory maintenance
- Australian National University, Australia
- Shanghai Jiao Tong University, China
- Fourth Military Medical University, China
- Qilu University of Technology, China
- University of Queensland, Australia
- Obstetrics and Gynecology Hospital of Fudan University, China
- University of Melbourne, Australia
Abstract
A defining feature of successful vaccination is the ability to induce long-lived antigen-specific memory cells. T follicular helper (Tfh) cells specialize in providing help to B cells in mounting protective humoral immunity in infection and after vaccination. Memory Tfh cells that retain the CXCR5 expression can confer protection through enhancing humoral response upon antigen re-exposure but how they are maintained is poorly understood. CXCR5+ memory Tfh cells in human blood are divided into Tfh1, Tfh2 and Tfh17 cells by the expression of chemokine receptors CXCR3 and CCR6 associated with Th1 and Th17 respectively. Here, we developed a new method to induce Tfh1, Tfh2 and Tfh17-like (iTfh1, iTfh2 and iTfh17) mouse cells in vitro. Although all three iTfh subsets efficiently support antibody responses in recipient mice with immediate immunization, iTfh17 cells are superior to iTfh1 and iTfh2 cells in supporting antibody response to a later immunization after extended resting in vivo to mimic memory maintenance. Notably, the counterpart human Tfh17 cells are selectively enriched in CCR7+ central memory Tfh cells with survival and proliferative advantages. Furthermore, the analysis of multiple human cohorts that received different vaccines for HBV, influenza virus, tetanus toxin or measles revealed that vaccine-specific Tfh17 cells outcompete Tfh1 or Tfh2 cells for the persistence in memory phase. Therefore, the complementary mouse and human results showing the advantage of Tfh17 cells in maintenance and memory function supports the notion that Tfh17-induced immunization might be preferable in vaccine development to confer long-term protection.
Data availability
Sequencing data have been deposited in GEO under the accession code GSE167309.
-
T Follicular Helper 17 (Tfh17) Cells are Superior for Immunological Memory MaintenanceNCBI Gene Expression Omnibus, GSE167309.
-
Imbalance of regulatory and cytotoxic SARS-CoV-2-reactive CD4+ T cells in COVID-19NCBI Gene Expression Omnibus, GSE152522.
-
Clonal replacement of tumor-specific T cells following PD-1 blockade [bulk RNA]NCBI Gene Expression Omnibus, GSE123812.
Article and author information
Author details
Katherine Kedzierska
Funding
National Health and Medical Research Council (GNT2009554,GNT200046,GNT1194036,GNT1158404,6)
- Thi HO Nguyen
- Katherine Kedzierska
- Ian A Cockburn
- Di Yu
National Natural Science Foundation of China (82130030,81920108011,82101198)
- Yin Yao
- Zheng Liu
National Key Research and Development Program of China (2017YFC0909003)
- Liangjing Lu
Natural Science Foundation of Shandong Province (ZR2020ZD41,2021ZDSYS12)
- Yunbo Wei
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were carried under protocols (ethics number: A2019/36) approved byANU's animal ethics committee.
Human subjects: Written informed consent was obtained from participants or the parents of children participants according to the ethics approved by human ethics committees of Renji Hospital affiliated to Shanghai Jiao Tong University School of Medicine (KY2019-161), Fourth Military Medical University (KY20163344-1), Tongji Hospital (NCT05009134), Shanghai Children's Medical Centre affiliated to Shanghai Jiao Tong University School of Medicine and Obstetrics and Gynecology Hospital of Fudan University (Kyy2018-6).
Copyright
© 2023, Gao et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,998
- views
-
- 469
- downloads
-
- 23
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
T follicular helper 17 (Tfh17) cells are superior for immunological memory maintenance
eLife 12:e82217.
https://doi.org/10.7554/eLife.82217
Further reading
-
- Immunology and Inflammation
The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has been increasing worldwide. Since gut-derived bacterial lipopolysaccharides (LPS) can travel via the portal vein to the liver and play an important role in producing hepatic pathology, it seemed possible that (1) LPS stimulates hepatic cells to accumulate lipid, and (2) inactivating LPS can be preventive. Acyloxyacyl hydrolase (AOAH), the eukaryotic lipase that inactivates LPS and oxidized phospholipids, is produced in the intestine, liver, and other organs. We fed mice either normal chow or a high-fat diet for 28 weeks and found that Aoah-/- mice accumulated more hepatic lipid than did Aoah+/+ mice. In young mice, before increased hepatic fat accumulation was observed, Aoah-/- mouse livers increased their abundance of sterol regulatory element-binding protein 1, and the expression of its target genes that promote fatty acid synthesis. Aoah-/- mice also increased hepatic expression of Cd36 and Fabp3, which mediate fatty acid uptake, and decreased expression of fatty acid-oxidation-related genes Acot2 and Ppara. Our results provide evidence that increasing AOAH abundance in the gut, bloodstream, and/or liver may be an effective strategy for preventing or treating MASLD.
-
- Immunology and Inflammation
- Microbiology and Infectious Disease
Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease in a variety of animal models. However, clinical trials of PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations of antibodies identified using protein-immunized animal systems and required extensive engineering to optimize binding and/or reduce immunogenicity. Of note, PA infections are common in people with cystic fibrosis (pwCF), who are generally believed to mount normal adaptive immune responses. Here, we utilized a tetramer reagent to detect and isolate PcrV-specific B cells in pwCF and, via single-cell sorting and paired-chain sequencing, identified the B cell receptor (BCR) variable region sequences that confer PcrV-specificity. We derived multiple high affinity anti-PcrV monoclonal antibodies (mAbs) from PcrV-specific B cells across three donors, including mAbs that exhibit potent anti-PA activity in a murine pneumonia model. This robust strategy for mAb discovery expands what is known about PA-specific B cells in pwCF and yields novel mAbs with potential for future clinical use.
