Cutting Edge: The RIG-I Ligand 3pRNA Potently Improves CTL Cross-Priming and Facilitates Antiviral Vaccination.

Protective immunity against intracellular pathogens involves the induction of robust CTL responses. Vaccination with protein Ags establishes such responses only when combined with immune-stimulatory adjuvants. In this study, we compared different adjuvants and identified triphosphate RNA (3pRNA) as especially effective at inducing CTL responses. 3pRNA sensing required IPS-1/MAVS signaling and induced type I IFN in plasmacytoid dendritic cells and macrophages, with the latter being more important for the adjuvant effect. Type I IFN acted on CD11c(+) cells, especially on CD8α(+) Batf3-dependent dendritic cells. Vaccination with OVA in combination with 3pRNA protected mice from a subsequent OVA-encoding adenovirus infection in a CD8(+) cell-dependent manner and more efficiently than other adjuvants. In summary, 3pRNA is a superior adjuvant for CTL activation and might be useful to facilitate antiviral immunization strategies.

German Society for Immunology and Australasian Society for Immunology joint Workshop 3(rd) -4(th) December 2015 - Meeting report.

The German Society for Immunology (DGfI) and the Australasian Society for Immunology (ASI) hosted the first DGfI-ASI joint workshop from December 3-4, 2015 in Canberra, Australia. A delegation of 15 distinguished German immunologists discussed the workshop topic "immune regulation in infections and immune mediated diseases" with the aim to establish new German-Australasian collaborations, discuss new concepts in the field of immune regulation and build a scientific network to create more utilizable resources for excellent (trans-border) immunological research. The workshop was associated with the 45(th) Annual Scientific Meeting of the ASI held from Nov 29-Dec 3, 2015, opening up even more opportunities for finding new collaboration partners. A return meeting will be linked to the annual DGfI meeting that will take place in 2017 in Erlangen.

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

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.

Batf3-dependent dendritic cells in the renal lymph node induce tolerance against circulating antigens.

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.

Cutting edge: CD25+ regulatory T cells prevent expansion and induce apoptosis of B cells specific for tissue autoantigens.

To study the role of CD25(+) regulatory T cells (T(regs)) in peripheral B cell tolerance, we generated transgenic rat insulin promoter RIP-OVA/HEL mice expressing the model Ags OVA and HEL in pancreatic islet beta cells (where RIP is rat insulin promoter and HEL is hen egg lysozyme). Adoptively transferred transgenic OVA-specific CD4(+) and CD8(+) T cells proliferated only in the autoantigen-draining pancreatic lymph node (PLN), demonstrating pancreas-specific Ag expression. Transferred HEL-specific transgenic B cells (IgHEL cells) disappeared within 3 wk from transgenic but not from nontransgenic mice immunized with autoantigen. Depletion of CD25(+) FoxP3(+) cells completely restored IgHEL cell numbers. T(reg) exerted an analogous suppressive effect on endogenous HEL-specific autoreactive B cells. T(regs) acted by inhibiting the proliferation of IgHEL cells in the spleen and PLN and by systemic induction of their apoptosis. Furthermore, they reduced BCR and MHC II surface expression on IgHEL cells in the PLN. These findings demonstrate that autoreactive B cells specific for a nonlymphoid tissue autoantigen are controlled by T(regs).

The Debate about Dendritic Cells and Macrophages in the Kidney.

The mononuclear phagocyte system includes macrophages and dendritic cells (DCs), which are usually classified by morphology, phenotypical characteristics, and function. In the last decades, large research communities have gathered substantial knowledge on the roles of these cells in immune homeostasis and anti-infectious defense. However, these communities developed to a degree independent from each other, so that the nomenclature and functions of the numerous DC and macrophage subsets overlap, resulting in the present intense debate about the correct nomenclature. This controversy has also reached the field of experimental nephrology. At present, no mutually accepted way to distinguish renal DC and macrophages is available, so that many important roles in acute and chronic kidney disease have been ascribed to both DCs and macrophages. In this perspective article, we discuss the causes and consequences of the overlapping DC-macrophage classification systems, functional roles of DCs and macrophages, and the transferability of recent findings from other disciplines to the renal mononuclear phagocyte system from the nephrologist's point of view.

The Role of Invariant Natural Killer T Cells in Dendritic Cell Licensing, Cross-Priming, and Memory CD8(+) T Cell Generation.

New vaccination strategies focus on achieving CD8(+) T cell (CTL) immunity rather than on induction of protective antibody responses. While the requirement of CD4(+) T (Th) cell help in dendritic cell (DC) activation and licensing, and in CTL memory induction has been described in several disease models, CTL responses may occur in a Th cell help-independent manner. Invariant natural killer T cells (iNKT cells) can substitute for Th cell help and license DC as well. iNKT cells produce a broad spectrum of Th1 and Th2 cytokines, thereby inducing a similar set of costimulatory molecules and cytokines in DC. This form of licensing differs from Th cell help by inducing other chemokines, while Th cell-licensed DCs produce CCR5 ligands, iNKT cell-licensed DCs produce CCL17, which attracts CCR4(+) CD8(+) T cells for subsequent activation. It has recently been shown that iNKT cells do not only enhance immune responses against bacterial pathogens or parasites but also play a role in viral infections. The inclusion of iNKT cell ligands in influenza virus vaccines enhanced memory CTL generation and protective immunity in a mouse model. This review will focus on the role of iNKT cells in the cross-talk with cross-priming DC and memory CD8(+) T cell formation.