Phenotype and functions of memory Tfh cells in human blood

Abstract

Our understanding of the origin and functions of human blood CXCR5(+) CD4(+) T cells found in human blood has changed dramatically in the past years. These cells are currently considered to represent a circulating memory compartment of T follicular helper (Tfh) lineage cells. Recent studies have shown that blood memory Tfh cells are composed of phenotypically and functionally distinct subsets. Here, we review the current understanding of human blood memory Tfh cells and the subsets within this compartment. We present a strategy to define these subsets based on cell surface profiles. Finally, we discuss how increased understanding of the biology of blood memory Tfh cells may contribute insight into the pathogenesis of autoimmune diseases and the mode of action of vaccines.

Keywords: T follicular helper cells; human blood; subsets.

Figure 1. The nine blood memory Tfh cell subsets defined by a three-dimensional analysis

(A) A three-dimensional analysis of human blood memory Tfh cells. The first parameter comprises CXCR3 and CCR6, which define Tfh1, Tfh2, and Tfh17 subsets. The second parameter includes PD-1 and CCR7, which define the PD-1⁻CCR7^hi and the PD-1⁺CCR7^int quiescent subpopulations within the blood memory Tfh1, Tfh2, and Tfh17 subsets. The third parameter is ICOS, which defines the ICOS⁺ activated population within the blood memory Tfh1, Tfh2, and Tfh17 subsets. The nine blood memory Tfh subsets defined by these parameters are indicated in a three-dimensional scale. (B) The nine blood memory Tfh subsets. The markers CXCR3 and CCR6 largely separate non-efficient helpers (Tfh1) and efficient helpers (Tfh2 and Tfh17). ICOS expression defines the quiescent subpopulations and the activated cells in each subset. The helper capacity of Tfh1 cells is limited to the activated ICOS⁺PD-1⁺⁺CCR7^lo subset that can help only memory B cells. While both quiescent subsets within Tfh2 and Tfh17 cells are capable of helping B cells, the ICOS⁻PD-1⁺CCR7^int subset provides a prompt help to memory B cells. Tfh2 and Tfh17 cells produce different sets of cytokines, and differentially regulate isotype switching. The intensity of the background orange color of each subset reflects the capacity to provide help to B cells.