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 8

Tfr cells can suppress GC B cells and do not require specific antigen for suppressive capacity.

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Tfr cells can suppress GC B cells and do not require specific antigen fo...
(A–D) Tfr cells suppress GC B cells. 3 × 104 Tfh cells and 1.5 × 104 Tfr cells or 1.5 × 104 non-Tfr Tregs (see Supplemental Figure 3) were cultured with 5 × 104 GC B cells (sorted as CD19+GL7+CD4– from the dLN of WT mice immunized 12 days previously with NP-OVA) in the presence of NP-OVA for 6 days. (A) Quantification of Ki67+ Tfh cells. (B) Quantification of IgG1+GL7+ B cells. (C) Quantification of GL7+ B cells. (D) Quantification of B7-1 expression on B cells. (E and F) In vitro antigen-specific suppression assays. 3 × 104 Tfh and 5 × 104 total B cells from the dLN of NP-OVA immunized mice were cultured with 1.5 × 104 dLN Tfr cells (sorted as CD4+ICOS+CXCR5+GITR+CD19–) from either NP-OVA– or NP-HEL–immunized mice in the presence of NP-OVA for 6 days. (E) B cell GL7 and IgG1 expression. Left: Representative plots pregated on CD19+IA+; number indicates percent of cells in gate. Right: Quantification. (F) Quantification of Ki67+ Tfh cells. Data indicate mean ± SEM of 3–4 replicate wells and are representative of 3 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001, 1-way ANOVA with Tukey post-test.