Disentangling Tfr cells from Treg cells and Tfh cells: How to untie the Gordian knot

Abstract

Legend has it that when Gordias, a peasant farmer, rode his oxcart into the capital he was proclaimed the new king of Phrygia by an oracle. In gratitude, he tied his oxcart to a post and dedicated it as an offering to Zeus. The knot was so intricate that it resisted all attempts to untie it, and the oracle prophesied that whoever could untie it would rule over all of Asia. In 333 BC, Alexander the Great came upon the knot and, realizing it had no free ends, took his sword and cut it free. Since their first description in 2004+ T follicular regulatory (Tfr) cells have also resisted all attempts to disentangle them from T follicular helper (Tfh) cells and regulatory T (Treg) cells (Fig. 1). In subsequent landmark studies, Tfr cells were defined as a subset of thymic-derived, FOXP3 + natural Treg cells that are dependent on BCL6 and expression of the chemokine receptor CXCR5 to localize in the germinal center (GC) of the B-cell follicle [2-4]. However, while there was initial consensus on the origin and phenotype of these cells, there was some disagreement on their actual role in the antibody response. This discrepancy may have arisen because these studies

Gut Commensal Segmented Filamentous Bacteria Fine-Tune T Follicular Regulatory Cells to Modify the Severity of Systemic Autoimmune Arthritis

“…In general, a suppressive role of Tfr cells on B cells in immunization or infection models has been observed. For example, in SRBC and NP-KLH immunization, Foxp3-Cre.Bcl6 fl/fl mice display increased anti-SRBC IgA (but reduced IgG) compared with WT controls (22). In another study, Foxp3-Cre.Bcl6 fl/fl mice display an increase of IgG2c Ab during influenza infection (but normal IgG1 and IgM) response (82).…”

“…Although Tfr cells have mainly been shown as a negative regulator for GC B cell and Ab responses, several recent studies indicate that the role of Tfr cells may vary based on models of studies (17)(18)(19)(22)(23)(24). In general, a suppressive role of Tfr cells on B cells in immunization or infection models has been observed.…”

“…By simultaneously obtaining the characteristics of both Treg and Tfh cells, Tfr cells have been shown to maintain a suppressive function and gain access to B cell follicles (17)(18)(19). However, recent studies unexpectedly found positive regulation of Tfr on GC B cell and Ab responses (22)(23)(24).…”

Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia

“…They induce B-cell differentiation and class-switching by ligation of CD40Ligand as well as T-cell-derived cytokines [46]. Another population of T-cells that augment the germinal center response are T follicular regulatory (Tfr) cells [47]. Tfr cells are a unique subset of Treg cells that are localized in the germinal center (GC) of the B-cell follicle.…”

Examination of the TIGIT, CD226, CD112, and CD155 Immune Checkpoint Molecules in Peripheral Blood Mononuclear Cells in Women Diagnosed with Early-Onset Preeclampsia

“…This surface receptor belongs to the poliovirus receptor (PVR) family and mediates inhibitory signals following the interaction with the ligands CD155 and CD112. The presence of the TIGIT receptor has been proved on the surface of activated αβ-T cells [ 15 ], Tregs [ 16 ], NKT, and NK cells [ 17 ]. As an inhibitory immune checkpoint molecule, the TIGIT mediated signal down-regulates the effector function of T cells [ 18 ] and T cell receptor expression [ 19 ], and decreases NK cell cytotoxicity and cytokine production [ 17 ].…”