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Introduction: Prophylactic vaccines generate strong and durable immunity to avoid future infections, whereas post-exposure vaccinations are intended to establish rapid protection against already ongoing infections. Antiviral cytotoxic CD8 + T cells (CTL) are activated by dendritic cells (DCs), which themselves must be activated by adjuvants to express costimulatory molecules and so-called signal 0-chemokines that attract naive CTL to the DCs., Hypothesis: Here we asked whether a vaccination protocol that combines two adjuvants, a toll-like receptor ligand (TLR) and a natural killer T cell activator, to induce two signal 0 chemokines, synergistically accelerates CTL activation., Methods: We used a well-characterized vaccination model based on the model antigen ovalbumin, the TLR9 ligand CpG and the NKT cell ligand α -galactosylceramide to induce signal 0-chemokines. Exploiting this vaccination model, we studied detailed T cell kinetics and T cell profiling in different in vivo mouse models of viral infection., Results: We found that CTL induced by both adjuvants obtained a head-start that allowed them to functionally differentiate further and generate higher numbers of protective CTL 1-2 days earlier. Such signal 0-optimized post-exposure vaccination hastened clearance of experimental adenovirus and cytomegalovirus infections., Conclusion: Our findings show that signal 0 chemokine-inducing adjuvant combinations gain time in the race against rapidly replicating microbes, which may be especially useful in post-exposure vaccination settings during viral epi/pandemics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Heine, Lemmermann, Flores, Becker-Gotot, Garbi, Brossart and Kurts.)

Introduction: SARS-CoV-2 infection results in varying disease severity, ranging from asymptomatic infection to severe illness. A detailed understanding of the immune response to SARS-CoV-2 is critical to unravel the causative factors underlying differences in disease severity and to develop optimal vaccines against new SARS-CoV-2 variants., Methods: We combined single-cell RNA and T cell receptor sequencing with CITE-seq antibodies to characterize the CD8 + T cell response to SARS-CoV-2 infection at high resolution and compared responses between mild and severe COVID-19., Results: We observed increased CD8 + T cell exhaustion in severe SARS-CoV-2 infection and identified a population of NK-like, terminally differentiated CD8 + effector T cells characterized by expression of FCGR3A (encoding CD16). Further characterization of NK-like CD8 + T cells revealed heterogeneity among CD16 + NK-like CD8 + T cells and profound differences in cytotoxicity, exhaustion, and NK-like differentiation between mild and severe disease conditions., Discussion: We propose a model in which differences in the surrounding inflammatory milieu lead to crucial differences in NK-like differentiation of CD8 + effector T cells, ultimately resulting in the appearance of NK-like CD8 + T cell populations of different functionality and pathogenicity. Our in-depth characterization of the CD8 + T cell-mediated response to SARS-CoV-2 infection provides a basis for further investigation of the importance of NK-like CD8 + T cells in COVID-19 severity., Competing Interests: Author JS-R declares funding from GSK and Sanofi and consultant fees from Travere Therapeutics, Owkin and Astex Pharmaceuticals unrelated to this study. Author SH has funding from Novo Nordisk. Author RK has grants from Travere Therapeutics, Galapagos, Chugai, and Novo Nordisk and is a consultant or received honoraria from Bayer, Pfizer, Novo Nordisk, Lilly-Pharma and Gruenenthal. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schreibing, Hannani, Kim, Nagai, Ticconi, Fewings, Bleckwehl, Begemann, Torow, Kuppe, Kurth, Kranz, Frank, Anslinger, Ziegler, Kraus, Enczmann, Balz, Windhofer, Balfanz, Kurts, Marx, Marx, Dreher, Schneider, Saez-Rodriguez, Costa, Hayat and Kramann.)

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.

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.

Dendritic cells (DCs) are the main inducers and regulators of cytotoxic T lymphocyte (CTL) responses against viruses and tumors. One checkpoint to avoid misguided CTL activation, which might damage healthy cells of the body, is the necessity for multiple activation signals, involving both antigenic as well as additional signals that reflect the presence of pathogens. DCs provide both signals when activated by ligands of pattern recognition receptors and "licensed" by helper lymphocytes. Recently, it has been established that such T cell licensing can be facilitated by CD4⁺ T helper cells ("classical licensing") or by natural killer T cells ("alternative licensing"). Licensing regulates the DC/CTL cross-talk at multiple layers. Direct recruitment of CTLs through chemokines released by licensed DCs has recently emerged as a common theme and has a crucial impact on the efficiency of CTL responses. Here, we discuss recent advances in our understanding of DC licensing for cross-priming and implications for the temporal and spatial regulation underlying this process. Future vaccination strategies will benefit from a deeper insight into the mechanisms that govern CTL activation.