Abstract
High-affinity antibody production depends on CD4+ T follicular helper (Tfh) cells. In humans, peripheral blood Tfh cells are heterogenous, as evidenced by differential expression of the chemokine receptors CXCR3 and CCR6, which to date have served to classify 3 subsets, pTfh1, pTfh2, and pTfh17. Although pTfh1 responses dominate during blood-stage Plasmodium infections, a clear association with protective antibody responses remains to be described. We hypothesized that pTfh cells exhibit greater phenotypic and functional heterogeneity than described by CXCR3/CCR6 and that more nuanced pTfh subsets play distinct roles during Plasmodium infection. We mapped pTfh cell heterogeneity in healthy individuals prior to and during controlled human malaria infection (CHMI) using parallel single-cell RNA-Seq and VDJ-Seq. We uncovered 2 pTfh1 subsets or differential phenotypic states, distinguishable by CCR7 expression. Prior to infection, Tfh1-CCR7– cells exhibited higher baseline expression of inflammatory cytokines and genes associated with cytotoxicity. Tfh1-CCR7+ cells had higher germinal center signatures. Indeed, during CHMI, Tfh1-CCR7+, Tfh1-CCR7–, and Tfh2 cells all clonally expanded and became activated. However, only Tfh1-CCR7+ and Tfh2 cells positively associated with protective antibody production. Hence, our data reveal further complexity among human Tfh cells and highlight 2 distinct subsets associated with antibody-mediated immunity to malaria.
Authors
Megan S.F. Soon, Damian A. Oyong, Nicholas L. Dooley, Reena Mukhiya, Zuleima Pava, Dean W. Andrew, Jessica R. Loughland, James S. McCarthy, Jo-Anne Chan, James G. Beeson, Christian R. Engwerda, Ashraful Haque, Michelle J. Boyle
This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.
Having trouble reading a PDF?
PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.
Having trouble saving a PDF?
Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.
Having trouble printing a PDF?
- Try printing one page at a time or to a newer printer.
- Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
- Make sure you are using the latest version of Adobe's Acrobat Reader.
