Acquisition of optimal TFH cell function is defined by specific molecular, positional, and TCR dynamic signatures.
Kartika PadhanEirini MoysiAlessandra NotoAlexander ChassiakosKhader GhneimMaria Maddalena PerraSanjana ShahVasilis PapaioannouGiulia FabozziDavid R AmbrozakAntigoni PoultsidiMaria IoannouCraig FenwickSamuel W DarkoDaniel C DouekRafick-Pierre SekalyGiuseppe PantaleoRichard A KoupConstantinos PetrovasPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
The development of follicular helper CD4 T (TFH) cells is a dynamic process resulting in a heterogenous pool of TFH subsets. However, the cellular and molecular determinants of this heterogeneity and the possible mechanistic links between them is not clear. We found that human TFH differentiation is associated with significant changes in phenotypic, chemokine, functional, metabolic and transcriptional profile. Furthermore, this differentiation was associated with distinct positioning to follicular proliferating B cells. Single-cell T cell receptor (TCR) clonotype analysis indicated the transitioning toward PD-1hiCD57hi phenotype. Furthermore, the differentiation of TFH cells was associated with significant reduction in TCR level and drastic changes in immunological synapse formation. TFH synapse lacks a tight cSMAC (central supra molecular activation Cluster) but displays the TCR in peripheral microclusters, which are potentially advantageous in the ability of germinal center (GC) B cells to receive necessary help. Our data reveal significant aspects of human TFH heterogeneity and suggest that the PD-1hiCD57hi TFH cells, in particular, are endowed with distinctive programming and spatial positioning for optimal GC B cell help.
Keyphrases
- single cell
- induced apoptosis
- regulatory t cells
- cell cycle arrest
- endothelial cells
- gene expression
- blood brain barrier
- rna seq
- dendritic cells
- oxidative stress
- immune response
- signaling pathway
- genome wide
- single molecule
- high throughput
- electronic health record
- pluripotent stem cells
- dna methylation
- mass spectrometry
- heat stress