Acquisition of optimal TFH cell function is defined by specific molecular, positional, and TCR dynamic signatures

Proc Natl Acad Sci U S A. 2021 May 4;118(18):e2016855118. doi: 10.1073/pnas.2016855118.

Abstract

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.

Keywords: TCR microclusters; TFH cell heterogeneity; immunological synapse.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • CD4-Positive T-Lymphocytes / immunology
  • CD57 Antigens / genetics
  • Cell Communication / immunology
  • Cell Differentiation / genetics*
  • Cell Differentiation / immunology
  • Cell Lineage / genetics
  • Cell Lineage / immunology*
  • Chemokines / genetics
  • Germinal Center / immunology
  • Germinal Center / metabolism
  • Humans
  • Immunological Synapses / genetics
  • Immunological Synapses / immunology
  • Lymphocyte Activation / immunology
  • Phenotype
  • Programmed Cell Death 1 Receptor / genetics
  • Receptors, Antigen, T-Cell / genetics*
  • Receptors, Antigen, T-Cell / immunology
  • T Follicular Helper Cells / immunology*
  • T Follicular Helper Cells / metabolism
  • T-Lymphocyte Subsets / immunology

Substances

  • CD57 Antigens
  • Chemokines
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell