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 5

Circulating Tfr and Tfh cells are memory-like cells that persist in vivo.

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Circulating Tfr and Tfh cells are memory-like cells that persist in vivo...
(A and B) Parabiosis experiments. (A) Actin-CFP Foxp3-GFP mice were immunized with NP-OVA and surgically joined via parabiosis to WT mice. 6 days after separation, the WT mate was immunized. (B) CFP+ population in basal or CD4+CXCR5+ populations in the dLN, nondraining cervical LN, spleen, blood, and skin. (C) Blood Tfr cells dominated the CXCR5+FOXP3+ population. Experiments were performed as in A, except actin-CFP Foxp3-GFP mice were joined with WT Foxp3-GFP mice. The indicated populations were analyzed for CFP chimerism and compared with the respective basal populations (CXCR5–FOXP3+ or CXCR5–FOXP3–) in the nondraining LN. Comparison of Tfr cell incidence between immunized mice and unimmunized controls is also shown. (D–I) Memory transfer experiments. Circulating Tfh and Tfr cells persisted for 30 days in vivo. (D) 2 × 104 blood CFP+ICOS+CXCR5+ (Tfr and Tfh) cells (see Supplemental Figure 3) from blood of immunized mice were transferred to recipients that were immunized 30 days later with NP-OVA. (E) Representative plots; number indicates percent of cells in gate. (F) CFP+ cells (percentage of CD4+ T cells) in dLN and in skin at the immunization site. (G) Tfr cells (percentage of CFP+ cells) in dLN. (H) CXCR5 expression on CFP+ cells in dLN. End, endogenous cells. (I) Transferred blood CD4+ Treg populations (percentage of total FOXP3+ cells). Data are pooled from 3 (A and B) or 5 (C) replicate surgeries, or pooled from 4 (D–F) or 2 (I) independent transfers. *P < 0.05, **P < 0.01, ***P < 0.001, unpaired Student’s t test.