Circulating T follicular regulatory and helper cells have memory-like properties
Peter T. Sage, David Alvarez, Jernej Godec, Ulrich H. von Andrian, Arlene H. Sharpe
Peter T. Sage, David Alvarez, Jernej Godec, Ulrich H. von Andrian, Arlene H. Sharpe
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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 7

Tfr cells suppress Tfh and B cells.

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Tfr cells suppress Tfh and B cells. (A–E) dLN Tfr suppression assays. 3 ...
(A–E) dLN Tfr suppression assays. 3 × 104 dLN Tfh cells (CD4+ICOS+CXCR5+GITR–CD19–; see Supplemental Figure 3) were plated with 1.5 × 104 Tfr cells (CD4+ICOS+CXCR5+GITR+CD19–) and either 5 × 104 B cells or 5 × 104 DCs (isolated from the dLN of WT immunized mice) for 5–6 days with anti-CD3 and anti-IgM. (A) Tfh cells were gated as CD4+CD19–FOXP3– and stained for CXCR5. (B and C) Tfh cells (cultured and gated as in A) were intracellularly stained for (B) BCL6 or (C) Ki67. (D) Intracellular cytokine staining in Tfh cells from suppression assays with B cells. (E) Quantification of IL-4 and IL-21 in culture supernatants. (F–J) 3 × 104 Tfh cells (CD4+ICOS+CXCR5+FOXP3–CD19–) and 5 × 104 B cells were plated with 1.5 × 104 Tfr cells (CD4+ICOS+CXCR5+FOXP3+CD19–) or 1.5 × 104 conventional dLN Tregs (CD4+ICOS–CXCR5–FOXP3+) for 6 days. (F) Ki67 in Tfh cells from cultures. Left: Plots pregated on CD4+FOXP3–CD19–; number indicates percent of cells in gate. Right: Quantification. (G) B cells were quantified for GL7 expression. (H) IgG1 expression in B cells. (I) Dose response of suppression of IgG1 expression in B cells cultured as indicated. (J) B7-1 expression on B cells. Data are mean ± SEM of 3–4 replicate wells and are representative of 3 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001, unpaired Student’s t test (A–E) or 1-way ANOVA with Tukey post-test (F–J).