Circulating T follicular regulatory and helper cells have memory-like properties
Peter T. Sage, … , Ulrich H. von Andrian, Arlene H. Sharpe
Peter T. Sage, … , Ulrich H. von Andrian, Arlene H. Sharpe
Published October 27, 2014
Citation Information: J Clin Invest. 2014;124(12):5191-5204. https://doi.org/10.1172/JCI76861.
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Research Article Immunology

Circulating T follicular regulatory and helper cells have memory-like properties

Abstract

Follicular Tregs (Tfr cells) inhibit antibody production, whereas follicular Th cells (Tfh cells) stimulate it. Tfr cells are found in blood; however, relatively little is known about the developmental signals for these cells or their functions. Here we demonstrated that circulating Tfr and Tfh cells share properties of memory cells and are distinct from effector Tfr and Tfh cells found within lymph nodes (LNs). Circulating memory-like Tfh cells were potently reactivated by DCs, homed to germinal centers, and produced more cytokines than did effector LN Tfh cells. Circulating memory-like Tfr cells persisted for long periods of time in vivo and homed to germinal centers after reactivation. Effector LN Tfr cells suppressed Tfh cell activation and production of cytokines, including IL-21, and inhibited class switch recombination and B cell activation. The suppressive function of this population was not dependent on specific antigen. Similar to LN effector Tfr cells, circulating Tfr cells also suppressed B and Tfh cells, but with a much lower capacity. Our data indicate that circulating memory-like Tfr cells are less suppressive than LN Tfr cells and circulating memory-like Tfh cells are more potent than LN effector Tfh cells; therefore, these circulating populations can provide rapid and robust systemic B cell help during secondary antigen exposure.

Authors

Peter T. Sage, David Alvarez, Jernej Godec, Ulrich H. von Andrian, Arlene H. Sharpe

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Figure 4

Circulating Tfr cells migrate to LNs and interact with GC B cells.

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Circulating Tfr cells migrate to LNs and interact with GC B cells. (A–C)...
(A–C) Actin-CFP Foxp3-GFP mice were immunized with NP-OVA, and 2 × 104 sorted blood CXCR5+ cells (containing Tfh and Tfr cells; see Supplemental Figure 3 for sorting) were transferred to Cd28–/– mice that were immunized with NP-OVA. (A) Transferred cells (CFP+) were identified 7 days later according to gates (iLN, inguinal dLN; aLN, axillary LN; cLN, cervical LN; mLN, mesenteric LN; Skin, skin at immunization site). Plots are pregated on CD4+CD19–; number indicates percent of cells in gate. (B) Dual-color overlay plots showing ICOS and CXCR5 expression on CFP+ transferred cells (red) or endogenous Cd28–/– CD4+ T cells (blue). Numbers indicate percent of cells in gate for each cell type. (C) Quantification of FOXP3+ cell percentage. (D) 1 × 104 blood Tfr cells from NP-OVA immunized CD45.2 mice were transferred to CD45.1 mice that were immunized. 7 days later, dLNs were stained for CD45.2 (blood Tfr), IgG1, and either IgD (left) or FOXP3 (right). Original magnification, ×200. (E) 2 × 104 blood Tfh cells from NP-OVA immunized CD45.2 mice were transferred to CD45.1 mice that were then immunized. 7 days later, dLNs were stained for CD45.2 (blood Tfh), IgD, and IgG1. Data are from transfers of Tfr or Tfh cells sorted from 20 pooled mice into a single recipient and are representative of ≥2 (A–C) or ≥3 (D and E) individual experiments. Scale bars: 20 μm; 5 μm (E, inset).