The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood

Abstract

Newly defined CD4+CXCR5+FoxP3+ T Follicular Regulatory (TFR) cells inhibit CD4+CXCR5+FoxP3− T Follicular Helper (TFH)-mediated humoral immunity. Although PD-1 is expressed by both cell types, the role of this inhibitory receptor on TFR differentiation is unknown. Here we show that PD-1/PD-L1 deficient mice have increased lymph node TFR cells, which have enhanced suppressive capacity. We also find substantial populations of TFR cells in mouse blood, and demonstrate that blood TFR cells home to lymph nodes and potently inhibit TFH cells in vivo. Blood TFR cells require CD28 and ICOS signaling, but are inhibited by PD-1/PD-L1. These findings reveal novel mechanisms by which the PD-1 pathway regulates antibody production and helps to reconcile inconsistencies surrounding the role of this pathway in humoral immunity.

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…However, regulatory CD4 + T cells are also found within GCs,235 and recent studies have shown that a subset of CXCR5 +  FoxP3 +  CD4 + Treg cells, termed T follicular regulatory (Tfr) cells, are generated as immune responses are induced and localize to the GC to control the GC response 236, 237, 238. In mice, Tfr cells have been shown to reduce antibody production and the number of GC B cells, antigen‐specific B cells, and plasma cells 236, 237, 238, 239, 240, 241. Multiple stages of the B‐cell differentiation process are inhibited, from initial B‐cell activation to the generation of class‐switched B cells and plasma cells.…”

“…Multiple stages of the B‐cell differentiation process are inhibited, from initial B‐cell activation to the generation of class‐switched B cells and plasma cells. Tfr cells also inhibit Tfh cell expansion, differentiation, and production of cytokines such as IL‐21 and IL‐4 239, 240, 242. Human Tfr cells (defined as CD127 −  CD25 +  CXCR5 +  CD4 + cells) have likewise been shown to reduce antibody production in in vitro Tfh:B cell co‐culture assays 243.…”

“…CXCR5 expression on FoxP3 + T cells is regulated by nuclear factor of activated T cells (NFAT) rather than Ascl2 246. Following their initial generation, Tfr cells may either leave the LN and enter the circulation to become memory Tfr cells242 or migrate into the B‐cell follicles where they interact with B cells and undergo full differentiation into effector Tfr cells 239. Tfr cell differentiation following interaction with both DCs and B cells requires co‐stimulation though CD28 and ICOS, and SAP‐dependent stimulation by B cells 236, 237, 239, 247, 248.…”

“…Tfr cell differentiation following interaction with both DCs and B cells requires co‐stimulation though CD28 and ICOS, and SAP‐dependent stimulation by B cells 236, 237, 239, 247, 248. CTLA‐4 expression on Tfr cells inhibits their differentiation and maintenance via interaction with CD80/86 on DCs and B cells240, 249; and PD‐1 ligation inhibits both Tfr cell differentiation and their subsequent function 239…”

“…CTLA‐4 has been shown to play an important role in Tfr cell function,240, 249 but the importance of other receptor‐ligand interactions and suppressive mechanisms such as production of IL‐10 and IL‐35, perforin/granzyme‐dependent lysis of GC Tfh and B cells, or interference with Tfh cell interaction with B cells remain to be elucidated. Antibody responses are determined by the ratio of Tfr:Tfh cells 239, 240, 250. In the resting state, there is a 1:1 ratio of Tfr:Tfh cells within CXCR5 +  CD4 + T cells in LNs (although lower ratios are present in the spleen and Peyer's patches).…”