The Coinhibitory Receptor CTLA-4 Controls B Cell Responses by Modulating T Follicular Helper, T Follicular Regulatory, and T Regulatory Cells

Abstract

Summary The receptor CTLA-4 has been implicated in controlling B cell responses, but the mechanisms by which CTLA-4 regulates antibody production are not known. Here we showed deletion of CTLA-4 in adult mice increased Tfh and Tfr cell numbers, and augmented B cell responses. In the effector phase, loss of CTLA-4 on Tfh cells resulted in heightened B cell responses, whereas loss of CTLA-4 on Tfr cells resulted in defective suppression of antigen-specific antibody responses. We also found that non-Tfr Treg cells could suppress B cells responses through CTLA-4, and that Treg and/or Tfr cells may downregulate B7-2 on B cells outside germinal centers as a means of suppression. Within the germinal center, however, Tfr cells potently suppress B cells through CTLA-4, but with a mechanism independent of altering B7-1 or B7-2. Thus, we identify multifaceted regulatory roles for CTLA-4 in Tfh, Tfr and Treg cells, which together control humoral immunity.

A distinct subpopulation of CD25−T-follicular regulatory cells localizes in the germinal centers

“…Despite down-regulation of some eTreg-associated genes, CD25 − Tfr cells maintained their expression of the majority of suppressive molecules, most critically CTLA-4, which we and others have demonstrated to have a key role in Tfr-dependent control of Tfh function (41)(42)(43). Notably many of the genes down-regulated in CD25 − Tfr cells, such as Klrg1, Itgae (CD103), Prdm1 (BLIMP-1), Il10, and Gzmb (Granzyme B), are IL-2-dependent (34).…”

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.…”

“…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).…”