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).
Reviewing Editor
- Tomohiro Kurosaki, Osaka University, Japan
Version history
- Received: July 27, 2022
- Preprint posted: July 31, 2022 (view preprint)
- Accepted: January 18, 2023
- Accepted Manuscript published: January 19, 2023 (version 1)
- Version of Record published: February 1, 2023 (version 2)
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
-
- 2,026
- Page views
-
- 337
- Downloads
-
- 3
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
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
-
- Cell Biology
- Immunology and Inflammation
Dendritic cells (DCs), the key antigen-presenting cells, are primary regulators of immune responses. Transcriptional regulation of DC development had been one of the major research interests in DC biology, however, the epigenetic regulatory mechanisms during DC development remains unclear. Here, we report that Histone deacetylase 3 (Hdac3), an important epigenetic regulator, is highly expressed in pDCs, and its deficiency profoundly impaired the development of pDCs. Significant disturbance of homeostasis of hematopoietic progenitors was also observed in HDAC3-deficient mice, manifested by altered cell numbers of these progenitors and defective differentiation potentials for pDCs. Using the in vitro Flt3L supplemented DC culture system, we further demonstrated that HDAC3 was required for the differentiation of pDCs from progenitors at all developmental stages. Mechanistically, HDAC3 deficiency resulted in enhanced expression of cDC1-associated genes, owing to markedly elevated H3K27 acetylation (H3K27ac) at these gene sites in BM pDCs. In contrast, the expression of pDC-associated genes was significantly downregulated, leading to defective pDC differentiation.
-
- Computational and Systems Biology
- Immunology and Inflammation
T cells are required to clear infection, and T cell motion plays a role in how quickly a T cell finds its target, from initial naive T cell activation by a dendritic cell to interaction with target cells in infected tissue. To better understand how different tissue environments affect T cell motility, we compared multiple features of T cell motion including speed, persistence, turning angle, directionality, and confinement of T cells moving in multiple murine tissues using microscopy. We quantitatively analyzed naive T cell motility within the lymph node and compared motility parameters with activated CD8 T cells moving within the villi of small intestine and lung under different activation conditions. Our motility analysis found that while the speeds and the overall displacement of T cells vary within all tissues analyzed, T cells in all tissues tended to persist at the same speed. Interestingly, we found that T cells in the lung show a marked population of T cells turning at close to 180o, while T cells in lymph nodes and villi do not exhibit this “reversing” movement. T cells in the lung also showed significantly decreased meandering ratios and increased confinement compared to T cells in lymph nodes and villi. These differences in motility patterns led to a decrease in the total volume scanned by T cells in lung compared to T cells in lymph node and villi. These results suggest that the tissue environment in which T cells move can impact the type of motility and ultimately, the efficiency of T cell search for target cells within specialized tissues such as the lung.
