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 1

Phenotype of circulating Tfh and Tfr cells.

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Phenotype of circulating Tfh and Tfr cells. (A–J) WT mice were immunized...
(A–J) WT mice were immunized s.c. with NP-OVA, and dLN and blood were analyzed for Tfh (A–E) and Tfr (F–J) cells on day 7. Unimm., unimmunized control. (A and F) Plots pregated on CD4+FOXP3–CD19– (A) or CD4+FOXP3+CD19– (F); number indicates percent in gate. (B and G) Quantification of cell subpopulations from plots. (C–E and H–J) Quantification of CXCR5 (C and H), ICOS (D and I), and Ki67 (E and J) expression. Total CD4+CD19– (Total CD4; C–E) and total CD4+FOXP3+CD19– cells (Total FOXP3+; H–J), are included as controls. (K) Tfh and Tfr cells in dLN and blood on d10 after PR8 influenza (PR8 Flu) infection. (L) Tfh and Tfr cells in spleen and blood on d7 after LCMV CL13 infection. Uninf., uninfected control. Data are mean ± SEM with 5 mice per group and representative of ≥3 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001, unpaired Student’s t test.