PD-1 Controls Follicular T Helper Cell Positioning and Function

Immunity. 2018 Aug 21;49(2):264-274.e4. doi: 10.1016/j.immuni.2018.06.012. Epub 2018 Jul 31.


Follicular T helper (Tfh) cells highly express the programmed cell death-1 (PD-1) molecule. Whereas inhibition of T cell receptor (TCR) signaling and CD28 co-stimulation is thought to be the primary mode of PD-1 functions, whether and how PD-1 regulates Tfh cell development and function is unclear. Here we showed that, when engaged by the ensemble of bystander B cells constitutively expressing PD-1 ligand 1 (PD-L1), PD-1 inhibited T cell recruitment into the follicle. This inhibition involved suppression of PI3K activities downstream of the follicle-guidance receptor CXCR5, was independent of co-signaling with the TCR, and necessitated ICOS signaling to overcome. PD-1 further restricted CXCR3 upregulation on Tfh cells, serving to concentrate these cells toward the germinal center territory, where PD-L1-PD-1 interactions between individual Tfh and B cells optimized B cell competition and affinity maturation. Therefore, operating in both costimulation-independent and -dependent manners, PD-1 controls tissue positioning and function of Tfh cells.

Keywords: CXCR3; ICOS; ICOSL; PD-1; PD-L1; Tfh cells; affinity maturation; follicular helper T cells; germinal center; motility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • B7-H1 Antigen / metabolism*
  • Cell Differentiation / immunology
  • Cell Line
  • Cell Movement / immunology
  • Female
  • Germinal Center / cytology*
  • Germinal Center / immunology
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Programmed Cell Death 1 Receptor / metabolism*
  • Receptors, CXCR3 / genetics
  • Receptors, CXCR5 / genetics
  • T-Lymphocytes, Helper-Inducer / cytology*
  • T-Lymphocytes, Helper-Inducer / immunology


  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, CXCR3
  • Receptors, CXCR5
  • Phosphatidylinositol 3-Kinases