Control of Germinal Center Responses by T-Follicular Regulatory Cells

Abstract

Regulatory T-cells (Treg cells), expressing the transcription factor Foxp3, have an essential role in the control of immune homeostasis. In order to control diverse types of immune responses Treg cells must themselves show functional heterogeneity to control different types of immune responses. Recent advances have made it clear that Treg cells are able to mirror the homing capabilities of known T-helper subtypes such as Th1, Th2, Th17, and T-follicular helper cells (Tfh), allowing them to travel to the sites of inflammation and deliver suppression in situ. One of the more recent discoveries in this category is the description of T-follicular regulatory (Tfr) cells, a specialized subset of Treg cells that control Tfh and resulting antibody responses. In this review we will discuss recent advances in our understanding of Tfr biology and the role of both Tfr and activated extra-follicular Tregs (eTreg) in the control of humoral immunity.

Keywords: T follicular helper (Tfh) cell; T follicular regulatory (Tfr) cell; autoimmunity; germinal center (GC); regulatory T-cells (Tregs).

Figure 1

Tfr and Tfh differentiation. Upon activation naïve CD25⁺ Tregs differentiate into activated effector Tregs in the T-cell zone or non-lymphoid tissues or early follicular resident CD25⁺Tfr. These CD25⁺Tfr can them downregulate CD25 expression causing the loss of BLIMP-1 expression and higher level BCL6 and CXCR5 expression, allowing these CD25⁻ Tfr to travel to the germinal center itself. All cell depicted are CD3⁺CD4⁺. Corresponding development of Tfh is also shown for contrast.

Figure 2

Role of different Treg subsets in control of the GC response. Model of potential differing roles for Tfr and Tregs in the control of humoral immunity. Tregs control the initial interaction of naïve T-cells with DCs, CD25⁺ Tfr control interactions at the T-B border and travel through the follicle, while CD25⁻ Tfr are responsible for direct suppression in the GC itself.

Figure 3

Expression of suppressive genes by Tfh, Tregs, CD25⁺ Tfr, and CD25⁻ Tfr. 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. Mice were vaccinated with NP-Ova in alum and cells sorted from peripheral lymph nodes 7 days later. CD4+B220– cells from Foxp3 reporter were sorted as CD62L⁻CXCR5⁺PD1⁺Foxp3⁻GITR⁻ Tfh, CD62L⁻CXCR5⁻Foxp3⁺GITR⁺CD25⁺ eTreg, CD62L⁻CXCR5⁺PD1⁺GITR⁺CD25⁺ CD25⁺ Tfr, and CD62L⁻CXCR5⁺PD1⁺Foxp3⁺GITR⁺CD25⁻ CD25⁻ Tfr.