B-lymphoid cells with attributes of dendritic cells regulate T cells via indoleamine 2,3-dioxygenase

Abstract

A discrete population of splenocytes with attributes of dendritic cells (DCs) and coexpressing the B-cell marker CD19 is uniquely competent to express the T-cell regulatory enzyme indoleamine 2,3-dioxygenase (IDO) in mice treated with TLR9 ligands (CpGs). Here we show that IDO-competent cells express the B-lineage commitment factor Pax5 and surface immunoglobulins. CD19 ablation abrogated IDO-dependent T-cell suppression by DCs, even though cells with phenotypic attributes matching IDO-competent cells developed normally and expressed IDO in response to interferon γ. Consequently, DCs and regulatory T cells (Tregs) did not acquire T-cell regulatory functions after TLR9 ligation, providing an alternative perspective on the known T-cell regulatory defects of CD19-deficient mice. DCs from B-cell-deficient mice expressed IDO and mediated T-cell suppression after TLR9 ligation, indicating that B-cell attributes were not essential for B-lymphoid IDO-competent cells to regulate T cells. Thus, IDO-competent cells constitute a distinctive B-lymphoid cell type with quintessential T-cell regulatory attributes and phenotypic features of both B cells and DCs. B cells | T-cell regulation | CD19I ndoleamine 2,3-dioxygenase (IDO) is an intracellular enzyme expressed in response to interferons (IFNs) at sites of inflammation. IDO inhibitors exacerbated T-cell-mediated pathology in models of tumor growth and autoimmune, infectious, and allergic diseases, and are currently under evaluation as potential tumor vaccine adjuvants in clinical settings (1, 2). By analogy to the tumor-protective effects of IDO, some pathogens may exploit IDO to facilitate persistence and IDO may attenuate vaccine-induced immunity (3-6). Consistent with this paradigm, artificially enhanced IDO activity attenuated graft versus host disease after bone marrow engraftment and prolonged rat lung allograft survival (7-9). Thus, IDO-dependent T-cell regulation occurs in multiple settings of chronic inflammation relevant to clinical syndromes.Despite the potential benefits of manipulating IDO activity to improve therapy in chronic inflammatory syndromes, little is known about the cellular basis of IDO-mediated T-cell regulation in physiologic settings. Antigen presenting cells (APCs) expressing IDO, such as dendritic cells (DCs), activate regulatory T cells (Tregs) and directly suppress effector T cells at sites of tissue inflammation (10, 11). Cells with functional and phenotypic attributes of DCs in mice and humans are competent to express IDO and regulate T-cell responses (11-15). In mice, splenocytes uniquely competent to mediate T-cell suppression via IDO after in vivo treatment with TLR9 ligands (CpGs) were a rare cell type located in splenic red pulp with phenotypic attributes of DCs (CD11c, CD8α, CD80/86, MHCII). IDO-competent cells also expressed B220 and the B-cell lineage marker CD19, but not the plasmacytoid DC (pDC) marker PDCA/120G8 (13). After CTLA4-Ig and CpG treatment, IDO-competent cells produced IFNα (15, 16), a functional attribute of pDCs and ...

Immunotherapy with Costimulatory Dendritic Cells To Control Autoimmune Inflammation

“…Thus, DC-encoded costimulation restores tolerance through a process of selfperpetuating peripheral regulation. IDO is an important mediator of tolerance, which is expressed by multiple APCs, including plasmacytoid DCs, macrophages, and B cells (16,48,(56)(57)(58). In DCs, IDO is induced by IFN-g and other T cell-derived signals, such as CD40L, GITR, and CTLA4 (15,48,50,59).…”

“…The expression of IDO by costimulatory DCs is further reinforced under conditions of immune activation, after reverse signaling by T cells through GITR ligand or CD80/CD86 or stimulation by IFN-g or TLR ligands. Recruitment of IDO + macrophages, B cells, and stromal cells also occurs through this mechanism (16,17).…”

Re-thinking the functions of IgA+plasma cells

“…105 Previously, a subset of splenic B cells that regulate T cell function through their expression of indoleamine 2,3-dioxygenase was shown to express CD11c. 106 As myeloid cells and B cells share a common developmental pathway, [107][108][109] it is possible that maintaining CD11c expression confers a selective advantage to specific B cell subsets. Although the expression of Ly6C and Ly6G are most frequently used to identify inflammatory monocytes and neutrophils, lymphocytes have been shown to express these proteins as well.…”

Emerging Concepts on Inhibitors of Indoleamine 2,3-Dioxygenase in Rheumatic Diseases

“…Whether expressed constitutively or following challenge with Toll-like receptor (TLR)-9 ligands, IDO favors the generation of adaptive Treg cells from naïve allogeneic CD4 + CD25 -T cells [18]. In mice, both CD19 + plasmacytoid DC (0.3-0.5% of total lymph node cells) [19] and Pax5 + B lymphoid cells with attributes of DC were reported to express IDO, both representing rare subsets of cells uniquely competent to mediate T-cell suppression [20]. Intriguingly, CD3 + CD4 + T cells may be a major source of IDO expression within the inflamed intestinal microenvironment of patients with graft-versus-host disease (GVHD) [21], suggesting that the spectrum of IDO-competent cell types is wider than initially appreciated and not confined to cells of the monocyte/macrophage or DC lineages.…”