Regulatory T cells use programmed death 1 ligands to directly suppress autoreactive B cells in vivo

Abstract

The mechanisms by which regulatory T cells (T regs ) suppress autoantibody production are unclear. Here we have addressed this question using transgenic mice expressing model antigens in the kidney. We report that T regs were essential and sufficient to suppress autoreactive B cells in an antigen-specific manner and to prevent them from producing autoantibodies. Most of this suppression was mediated through the inhibitory cell-surface-molecule programmed death-1 (PD-1). Suppression required PD-1 expression on autoreactive B cells and expression of the two PD-1 ligands on T regs . PD-1 ligation inhibited activation of autoreactive B cells, suppressed their proliferation, and induced their apoptosis. Intermediate PD-1 + cells, such as T helper cells, were dispensable for suppression. These findings demonstrate in vivo that T regs use PD-1 ligands to directly suppress autoreactive B cells, and they identify a previously undescribed peripheral B-cell tolerance mechanism against tissue autoantigens. Regulatory T cells (T regs ) are powerful suppressors of autoreactive T cells with high therapeutic potential (1-3). T regs also suppress auto-Ab production (4, 5). We recently showed in vivo that they do so in an antigen-specific (Ag-specific) manner (6, 7). These studies used rat insulin promoter HEL/OVA (ROH) mice expressing ovalbumin (OVA) and hen egg lysozyme (HEL) in pancreatic islet β-cells. Autoreactive OVA-and HEL-specific B cells, but not B cells specific for a foreign antigen, failed to proliferate in response to in vivo autoantigen (auto-Ag) challenge and instead underwent apoptosis in a strictly T reg -dependent fashion. T regs can affect B cells indirectly by suppressing the T-helper (Th) cells required for antibody production (8, 9). This did not rule out that T regs might also suppress B cells directly. Cell culture systems have revealed that CD25 + T regs can kill cocultured B cells (10-12). A recent in vivo study showed that T regs enter germinal centers and suppress B cells in this site (13,14). The question whether this occurred directly or indirectly remained open (15). This question is difficult to address in vivo because it requires an experimental system where T regs can suppress B cells but not Th cells.Another open question concerns the molecular mechanisms by which T regs suppress. In principle, T regs may suppress other T cells by (i) secreting inhibitory mediators; (ii) deprivation of survival factors; (iii) killing target cells by granzyme/perforin; and (iv) modulation of DCs by ligating inhibitory T-cell receptors (16,17). The exact contribution of these mechanisms in relevant in vivo situations and the mechanisms by which T regs suppress are unclear.Programmed death-1 (PD-1, CD279) is an activation-induced member of the extended CD28/CTLA-4 family that suppresses T cells (18-21). It has been associated with exhausted memory T cells in chronic viral infection (22,23) and with cytotoxic T-cell cross-tolerance (24). PD-1 has two known ligands, PDL-1 (B7-H1, CD274) and PDL-2 (B7-DC, CD273) (25,...

A Recombinant G Protein Plus Cyclosporine A–Based Respiratory Syncytial Virus Vaccine Elicits Humoral and Regulatory T Cell Responses against Infection without Vaccine-Enhanced Disease

“…However, we speculate that the mechanism by which CSA enhanced Ab production here may be indirect and via induction of Treg cells. There are contradictory reports of Treg effects on B cell function; that is, there may be suppression of B cells in one circumstance (101)(102)(103), but help for B cells in another (104)(105)(106). Help for B cells might be a consequence of IL-10 production by induced Treg cells.…”

Batf3-Dependent Dendritic Cells in the Renal Lymph Node Induce Tolerance against Circulating Antigens

“…7,8 We recently showed that regulatory T cells use PD-1 ligands to directly tolerize B cells specific for glomerular autoantigen. 9 The role of PD-1 in renal disease is unclear.…”

“…For immunogenic immunization, 50 mg of OVA and 10 mg of CpG ODN1668 in a total volume of 200 ml were injected subcutaneously into the flank. PD-L1 and PD-L2 were blocked as recently described, by intraperitoneally injecting 250 mg of MIH5 or TY25, 9,33 respectively, on the day before and on the day of immunization.…”

Regulation of the Intrahepatic CD8+ T Lymphocyte

“…Moreover, PD-L1 expression by T reg cells has been reported to play a role in mediating suppressor function in some laboratories [179][180][181] .…”

“…Currently, it is established that foreign antigen, IL-2, IL-10, TGF-β, galectin-9 (Gal-9), and/or PD-1/PD-L1 signaling can influence the differentiation of iT reg cells 80,[83][84][85]167,168 . Further, suppression of T cell responses is mediated through a variety of antigen-specific cell contact dependent and independent mechanisms including IL-2 sequestration 169 , release of anti-inflammatory cytokines (IL-10 and TGF-β) 53,54,165,[170][171][172] , chemokine production (CCL4) 173 , CTLA-4 co-stimulation 174 , Fas/FasL or perforin killing [175][176][177] , granzyme B (GrB) negative feedback loops 178 , and negative PD-1/PD-L1 signaling [179][180][181] . Fig.…”