Ontogeny of different subsets of yellow fever virus-specific circulatory CXCR5+ CD4+ T cells after yellow fever vaccination

Quinn Degottardi,Eddie A James,William W Kwok,Junbao Yang,Theresa J Gates,Michael Fehlings,I-Ting Chow,Uma Malhotra,Hannah A Deberg,Yannick Simoni,Evan W Newell

doi:10.1038/s41598-020-72610-6

Abstract

Monitoring the frequency of circulatory CXCR5+ (cCXCR5+) CD4+ T cells in periphery blood provides a potential biomarker to draw inferences about T follicular helper (TFH) activity within germinal center. However, cCXCR5+ T cells are highly heterogeneous in their expression of ICOS, PD1 and CD38 and the relationship between different cCXCR5 subsets as delineated by these markers remains unclear. We applied class II tetramer reagents and mass cytometry to investigate the ontogeny of different subsets of cCXCR5+ T cell following yellow fever immunization. Through unsupervised analyses of mass cytometry data, we show yellow fever virus-specific cCXCR5 T cells elicited by vaccination were initially CD38+ICOS+PD1+, but then transitioned to become CD38+ICOS−PD1+ and CD38−ICOS−PD1+ before coming to rest as a CD38−ICOS−PD1− subset. These results imply that most antigen-specific cCXCR5+ T cells, including the CD38−ICOS−PD1− CXCR5+ T cells are derived from the CXCR5+CD38+ICOS+PD1+ subset, the subset that most resembles preTFH/TFH in the germinal center.

Highlights

Monitoring the frequency of circulatory CXCR5+ (cCXCR5+) CD4+ T cells in periphery blood provides a potential biomarker to draw inferences about T follicular helper (TFH) activity within germinal center
Pre-TFH and T FH cells which are found in the T cell-B cell interface and the germinal centers of secondary lymphoid tissues respectively are characterized by the elevated cell surface expression of CXCR5, ICOS, PD1 and intracellular expression of the lineage defining transcription factor BCL-62–4
YF-Vax elicited a high proportion of yellow fever virus (YFV)-specific cCXCR5+ T cells, such that nearly 50% of CD4+ YFV ENV-reactive T cells were CXCR5+ 60 days after vaccination

Summary

Introduction

Monitoring the frequency of circulatory CXCR5+ (cCXCR5+) CD4+ T cells in periphery blood provides a potential biomarker to draw inferences about T follicular helper (TFH) activity within germinal center. Through unsupervised analyses of mass cytometry data, we show yellow fever virus-specific cCXCR5 T cells elicited by vaccination were initially CD38+ICOS+PD1+, but transitioned to become CD38+ICOS−PD1+ and CD38−ICOS−PD1+ before coming to rest as a CD38−ICOS−PD1− subset. These results imply that most antigen-specific cCXCR5+ T cells, including the CD38−ICOS−PD1− CXCR5+ T cells are derived from the CXCR5+CD38+ICOS+PD1+ subset, the subset that most resembles preTFH/TFH in the germinal center. More recent data show TCR clonotype sharing between c CXCR5+ T cells and thoracic duct C XCR5+ T cells and similarity between transcriptome and epigenetic profiles between GC-TFH and thoracic duct CXCR5+, suggesting that GC-TFH transit through the thoracic duct as CXCR5-bright PD1-bright T cells before entering the peripheral blood as cCXCR5+ T cells[14]

Methods

Results

Conclusion