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 December 1, 2014; First 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 2

Circulating Tfr cells require DCs for development.

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Circulating Tfr cells require DCs for development. (A–C) B cells are not...
(A–C) B cells are not required for circulating Tfr and Tfh cell differentiation. WT or μMT mice were immunized s.c. with NP-OVA; 7 days later, CD4+ICOS+CXCR5+ cells were analyzed. (A) Representative plots (pregated on CD4+CD19–; number indicates percent in gate) and quantification. (B) Tfr (CD4+ICOS+CXCR5+FOXP3+CD19–) and (C) Tfh (CD4+ICOS+CXCR5+FOXP3–CD19–) cells after immunization. (D and E) WT or CD11c-DTR BM chimeras were immunized s.c. with NP-OVA, and DT was administered on d0, d2, d4, and d6. (D) dLN analysis of CD11c+MHCII+ DCs; number indicates percent of cells in gate. (E) Quantification of Ki67+ Tfr cells (percentage of total FOXP3+ cells) and Ki67+ Tfh cells (percentage of total CD4+ T cells) in dLN and blood. (F–H) DC transfer experiments. WT BMDCs were pulsed with NP-OVA and transferred s.c. to WT mice (DC Trans); 7 days later, dLNs and blood were analyzed. WT mice that received no transfer were included as controls. (F) Representative plots (pregated on CD4+CD19–; number indicates percent of cells in gate). (G and H) Quantification of dLN and blood Tfr (G) and Tfh (H) cells. Data are mean ± SEM with 5 mice per group and representative of ≥3 independent experiments. **P < 0.01, ***P < 0.001, unpaired Student’s t test.