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 6

Circulating Tfh cells require DCs for enhanced cytokine production.

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Circulating Tfh cells require DCs for enhanced cytokine production. (A) ...
(A) In vitro activation assay. dLN or blood Tfh cells (sorted as CD4+ICOS+CXCR5+GITR–CD19–; see Supplemental Figure 3) were plated with B cells or CD11c+MHCII+ DCs (sorted from dLN of WT immunized mice) plus anti-IgM and anti-CD3 for 6 days. Left: Plots pregated on CD4+CD19–; number indicates percent of cells in gate. Right: Quantification of BCL6+Ki67+ cells. (B and C) Intracellular cytokine staining of Tfh cells from cocultures with B cells or DCs as in A, except samples were stimulated with PMA/ionomycin for 4 hours in the presence of Golgistop prior to staining. (B) Representative plots; numbers indicate percentage of cells in the each respective quadrant. (C) Quantification. (D) Quantification of cytokines measured in culture supernatants of cultures as in A. ND, not detected. Graphs represent mean ± SEM of pooled data from 3 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001, unpaired Student’s t test (C and D) or 1-way ANOVA with Tukey post-test (A).