A distinct subpopulation of CD25⁻T-follicular regulatory cells localizes in the germinal centers

Abstract

T-follicular helper (Tfh) cells differentiate through a multistep process, culminating in germinal center (GC) localized GC-Tfh cells that provide support to GC-B cells. T-follicular regulatory (Tfr) cells have critical roles in the control of Tfh cells and GC formation. Although Tfh-cell differentiation is inhibited by IL-2, regulatory T (Treg) cell differentiation and survival depend on it. Here, we describe a CD25− subpopulation within both murine and human PD1+CXCR5+Foxp3+ Tfr cells. It is preferentially located in the GC and can be clearly differentiated from CD25+ non–GC-Tfr, Tfh, and effector Treg (eTreg) cells by the expression of a wide range of molecules. In comparison to CD25+ Tfr and eTreg cells, CD25− Tfr cells partially down-regulate IL-2–dependent canonical Treg features, but retain suppressive function, while simultaneously up-regulating genes associated with Tfh and GC-Tfh cells. We suggest that, similar to Tfh cells, Tfr cells follow a differentiation pathway generating a mature GC-localized subpopulation, CD25− Tfr cells.

T follicular regulatory (Tfr) cells: Dissecting the complexity of Tfr‐cell compartments

“…35,69,70 Wing and colleagues showed that following immunization both CD25 − and CD25 + Tfr cells emerge with the CD25 − Tfr cells preferentially locating within GCs. 35,69,70 Wing and colleagues showed that following immunization both CD25 − and CD25 + Tfr cells emerge with the CD25 − Tfr cells preferentially locating within GCs.…”

“…35,69,70 Wing and colleagues showed that following immunization both CD25 − and CD25 + Tfr cells emerge with the CD25 − Tfr cells preferentially locating within GCs. 69 Moreover, CD25 − Tfr cells presented a gene expression profile more similar to the one of Tfh cells. 69 In tissue sections, there was a greater number of CD25 -Foxp3 + T cells within GC, although some CD25 + Foxp3 + T cells could also be found.…”

“…However, while CD25 + Tfr cells persist after the peak of GC reaction, CD25 − Tfr cells followed a kinetic response similar to Tfh cells (albeit with a later peak), suggesting that only CD25 − Tfr cells followed a GC-like kinetic response. 69 To specifically address the impact of IL-2 on Tfr cells, Ritvo and colleagues 70 used Foxp3 GFP reporter mice infected with adeno-associated virus coding for IL-2 (to maintain continuous high levels of IL-2) prior to OVA immunization. 69 Moreover, CD25 − Tfr cells presented a gene expression profile more similar to the one of Tfh cells.…”

Control of Germinal Center Responses by T-Follicular Regulatory Cells

“…RNA expression of murine Tfr cells measured as Fragments Per Kilobase Million (FPKM) taken from RNAseq dataset in Wing et al (26). n = 2 ±SEM.…”

The immune cell landscape in kidneys of lupus nephritis patients

“…The clustering together of TFH-like cells and FoxP3 + Helios + regulatory T cells further raises the possibility that T follicular regulatory cells are also present 43,44 . A distinct set of effector CD4 + T cells could be …”