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

Abstract

Although the spleen is a major site where immune tolerance to circulating innocuous antigens occurs, the kidney also contributes. Circulating antigens smaller than albumin are constitutively filtered and concentrated in the kidney and reach the renal lymph node by lymphatic drainage, where resident dendritic cells (DCs) capture them and induce tolerance of specific cytotoxic T cells through unknown mechanisms. Here, we found that the coinhibitory cell surface receptor programmed death 1 (PD-1) on cytotoxic T cells mediates to their tolerance. Renal lymph node DCs of the CD8 + XCR1 + subset, which depend on the transcription factor Batf3, expressed the PD-1 cognate ligand PD-L1. Batf3-dependent DCs in the renal lymph node presented antigen that had been concentrated in the kidney and used PD-L1 to induce apoptosis of cytotoxic T cells. In contrast, T cell tolerance in the spleen was independent of PD-1, PD-L1, and Batf3. In summary, these results clarify how the kidney/renal lymph node system tolerizes the immune system against circulating innocuous antigens.

Dendritic Cells and Macrophages

“…It is unclear whether DCs do so by extending dendrites between epithelial cells into the tubular lumen as described for the intestine (51). In the absence of PAMPs, DCs express the suppressive molecule PDL-1 that induces apoptosis in T cells specific for such antigens (52). This function may serve to maintain immunologic tolerance against renal autoantigens or innocuous circulating small molecular weight antigens.…”

The Renal Lymph Node and Immune Tolerance to Filtered Antigens

“…3 In a simple but revealing first experiment, Gottschalk et al 3 show that fluorescent ovalbumin is taken up within 10 minutes of intravenous injection by a substantially higher proportion of the DCs in renal lymph nodes (RLNs) than other lymph nodes. The timing of this observation, together with previously published work from the same group, 4 indicates that intravascular ovalbumin is filtered in the kidney and reabsorbed into the interstitium from where it is quickly carried by lymphatics to the RLN and internalized by DC populations resident there.…”

“…Using more complex experimental approaches, Gottschalk et al 3 have also provided quite clear and convincing answers to these questions. In the first place, a role for the negative regulatory cell surface protein programmed death ligand 1 (PD-L1) was shown through the use of blocking antibodies and OT-1 cells derived from mice genetically lacking the PD-L1 binding partner PD-1.…”

“…In the second place, a subpopulation of DCs that is characterized by the surface marker phenotype CD11b 2 / CD8 1 /CD103 1 /XCR1 1 was shown to internalize filtered ovalbumin in the RLN, inherently express PD-L1, and play an essential role in tolerizing OT-1 cells by PD-L1. In proving the latter point, Gottschalk et al 3 took advantage of the observation that the protein basic leucine zipper transcription factor, activating transcription factor-like 3 (Batf3), is required for development of crosspriming CD8…”

“…As the experiments of Gottschalk et al 3 show, circulating antigens may induce a form of peripheral immune tolerance that is sustained through clonal deletion and/or inactivation of lymphocytes. 3 Their results support a model, whereby binding of PD-1 on the T cell by PD-L1 expressed by the presenting DC during primary antigen encounter mediates proapoptotic and proanergic intracellular signaling within the T cell.…”