Systemic inflammatory response syndrome triggered by blood-borne pathogens induces prolonged dendritic cell paralysis and immunosuppression.

Blood-borne pathogens can cause systemic inflammatory response syndrome (SIRS) followed by protracted, potentially lethal immunosuppression. The mechanisms responsible for impaired immunity post-SIRS remain unclear. We show that SIRS triggered by pathogen mimics or malaria infection leads to functional paralysis of conventional dendritic cells (cDCs).

mRNA vaccine against malaria tailored for liver-resident memory T cells.

Malaria is caused by Plasmodium species transmitted by Anopheles mosquitoes. Following a mosquito bite, Plasmodium sporozoites migrate from skin to liver, where extensive replication occurs, emerging later as merozoites that can infect red blood cells and cause symptoms of disease. As liver tissue-resident memory T cells (Trm cells) have recently been shown to control liver-stage infections, we embarked on a messenger RNA (mRNA)-based vaccine strategy to induce liver Trm cells to prevent malaria.

Interplay between liver and blood stages of Plasmodium infection dictates malaria severity via γδ T cells and IL-17-promoted stress erythropoiesis.

Plasmodium replicates within the liver prior to reaching the bloodstream and infecting red blood cells. Because clinical manifestations of malaria only arise during the blood stage of infection, a perception exists that liver infection does not impact disease pathology. By developing a murine model where the liver and blood stages of infection are uncoupled, we showed that the integration of signals from both stages dictated mortality outcomes.

Complexing CpG adjuvants with cationic liposomes enhances vaccine-induced formation of liver T cells.

Tissue resident memory T cells (T cells) can provide effective tissue surveillance and can respond rapidly to infection. Vaccination strategies aimed at generating T cells have shown promise against a range of pathogens. We have previously shown that the choice of adjuvant critically influences CD8 T cell formation in the liver.

Hsp90 contains a natural immunogenic I-A-restricted antigen common to rodent and human species.

Thorough understanding of the role of CD4 T cells in immunity can be greatly assisted by the study of responses to defined specificities. This requires knowledge of -derived immunogenic epitopes, of which only a few have been identified, especially for the mouse C57BL/6 background. We recently developed a TCR transgenic mouse line, termed PbT-II, that produces CD4 T cells specific for an MHC class II (I-A)-restricted epitope and is responsive to both sporozoites and blood-stage .

The Batman and Robin of liver-stage immunity to malaria.

Malaria parasites replicate within the liver shortly after infection. This stage can be controlled by CD8 T cells, but which subsets undertake this function is unclear. Lefebvre et al.

Type I interferon production elicits differential CD4+ T-cell responses in mice infected with Plasmodium berghei ANKA and P. chabaudi.

Plasmodium parasites that infect humans are highly polymorphic, and induce various infections ranging from an asymptomatic state to life-threatening diseases. However, how the differences between the parasites affect host immune responses during blood-stage infection remains largely unknown. We investigated the CD4+ T-cell immune responses in mice infected with P.

Elucidating the Motif for CpG Oligonucleotide Binding to the Dendritic Cell Receptor DEC-205 Leads to Improved Adjuvants for Liver-Resident Memory.

DEC-205 is a cell-surface receptor that transports bound ligands into the endocytic pathway for degradation or release within lysosomal endosomes. This receptor has been reported to bind a number of ligands, including keratin, and some classes of CpG oligodeoxynucleotides (ODN). In this study, we explore in detail the requirements for binding ODNs, revealing that DEC-205 efficiently binds single-stranded, phosphorothioated ODN of ≥14 bases, with preference for the DNA base thymidine, but with no requirement for a CpG motif.

Hemozoin-mediated inflammasome activation limits long-lived anti-malarial immunity.

During acute malaria, most individuals mount robust inflammatory responses that limit parasite burden. However, long-lived sterilizing anti-malarial memory responses are not efficiently induced, even following repeated Plasmodium exposures. Using multiple Plasmodium species, genetically modified parasites, and combinations of host genetic and pharmacologic approaches, we find that the deposition of the malarial pigment hemozoin directly limits the abundance and capacity of conventional type 1 dendritic cells to prime helper T cell responses.

CD8 and CD4 T Cells Infiltrate into the Brain during ANKA Infection and Form Long-Term Resident Memory.

In the ANKA mouse model of malaria, accumulation of CD8 T cells and infected RBCs in the brain promotes the development of experimental cerebral malaria (ECM). In this study, we used malaria-specific transgenic CD4 and CD8 T cells to track evolution of T cell immunity during the acute and memory phases of ANKA infection. Using a combination of techniques, including intravital multiphoton and confocal microscopy and flow cytometric analysis, we showed that, shortly before onset of ECM, both CD4 and CD8 T cell populations exit the spleen and begin infiltrating the brain blood vessels.

CD49d marks Th1 and Tfh-like antigen-specific CD4+ T cells during Plasmodium chabaudi infection.

Upon activation, specific CD4+ T cells up-regulate the expression of CD11a and CD49d, surrogate markers of pathogen-specific CD4+ T cells. However, using T-cell receptor transgenic mice specific for a Plasmodium antigen, termed PbT-II, we found that activated CD4+ T cells develop not only to CD11ahiCD49dhi cells, but also to CD11ahiCD49dlo cells during acute Plasmodium infection. CD49dhi PbT-II cells, localized in the red pulp of spleens, expressed transcription factor T-bet and produced IFN-γ, indicating that they were type 1 helper T (Th1)-type cells.

Extrafollicular CD4 T cell-derived IL-10 functions rapidly and transiently to support anti-Plasmodium humoral immunity.

Immunity against malaria depends on germinal center (GC)-derived antibody responses that are orchestrated by T follicular helper (TFH) cells. Emerging data show that the regulatory cytokine IL-10 plays an essential role in promoting GC B cell responses during both experimental malaria and virus infections. Here we investigated the cellular source and temporal role of IL-10, and whether IL-10 additionally signals to CD4 T-cells to support anti-Plasmodium humoral immunity.

Harnessing liver-resident memory T cells for protection against malaria.

Introduction: Tissue-resident memory T cells (T cells) are powerful mediators of protracted adaptive immunity to infection in peripheral organs. Harnessing T cells through vaccination hence promises unprecedented potential for protection against infection. A paramount example of this is malaria, a major infectious disease for which immunity through traditional vaccination strategies remains challenging.

Development of Plasmodium-specific liver-resident memory CD8 T cells after heat-killed sporozoite immunization in mice.

Malaria remains a major cause of mortality in the world and an efficient vaccine is the best chance of reducing the disease burden. Vaccination strategies for the liver stage of disease that utilise injection of live radiation-attenuated sporozoites (RAS) confer sterile immunity, which is mediated by CD8 memory T cells, with liver-resident memory T cells (T ) being particularly important. We have previously described a TCR transgenic mouse, termed PbT-I, where all CD8 T cells recognize a specific peptide from Plasmodium.

Resident Memory T Cells and Their Role within the Liver.

Immunological memory is fundamental to maintain immunity against re-invading pathogens. It is the basis for prolonged protection induced by vaccines and can be mediated by humoral or cellular responses-the latter largely mediated by T cells. Memory T cells belong to different subsets with specialized functions and distributions within the body.

Display of Native Antigen on cDC1 That Have Spatial Access to Both T and B Cells Underlies Efficient Humoral Vaccination.

Follicular dendritic cells and macrophages have been strongly implicated in presentation of native Ag to B cells. This property has also occasionally been attributed to conventional dendritic cells (cDC) but is generally masked by their essential role in T cell priming. cDC can be divided into two main subsets, cDC1 and cDC2, with recent evidence suggesting that cDC2 are primarily responsible for initiating B cell and T follicular helper responses.

Glycolipid-peptide vaccination induces liver-resident memory CD8 T cells that protect against rodent malaria.

Liver resident-memory CD8 T cells (T cells) can kill liver-stage -infected cells and prevent malaria, but simple vaccines for generating this important immune population are lacking. Here, we report the development of a fully synthetic self-adjuvanting glycolipid-peptide conjugate vaccine designed to efficiently induce liver T cells. Upon cleavage in vivo, the glycolipid-peptide conjugate vaccine releases an MHC I-restricted peptide epitope (to stimulate -specific CD8 T cells) and an adjuvant component, the NKT cell agonist α-galactosylceramide (α-GalCer).

A Natural Peptide Antigen within the Plasmodium Ribosomal Protein RPL6 Confers Liver T Cell-Mediated Immunity against Malaria in Mice.

Liver-resident memory CD8 T (T) cells remain in and constantly patrol the liver to elicit rapid immunity upon antigen encounter and can mediate efficient protection against liver-stage Plasmodium infection. This finding has prompted the development of immunization strategies where T cells are activated in the spleen and then trapped in the liver to form T cells. Here, we identify PbRPL6, a H2-K-restricted epitope from the putative 60S ribosomal protein L6 (RPL6) of Plasmodium berghei ANKA, as an optimal antigen for endogenous liver T cell generation and protection against malaria.

Microbiota-Derived Short-Chain Fatty Acids Promote the Memory Potential of Antigen-Activated CD8 T Cells.

Interactions with the microbiota influence many aspects of immunity, including immune cell development, differentiation, and function. Here, we examined the impact of the microbiota on CD8 T cell memory. Antigen-activated CD8 T cells transferred into germ-free mice failed to transition into long-lived memory cells and had transcriptional impairments in core genes associated with oxidative metabolism.

CD8 T Cell Activation Leads to Constitutive Formation of Liver Tissue-Resident Memory T Cells that Seed a Large and Flexible Niche in the Liver.

Liver tissue-resident memory T (Trm) cells migrate throughout the sinusoids and are capable of protecting against malaria sporozoite challenge. To gain an understanding of liver Trm cell development, we examined various conditions for their formation. Although liver Trm cells were found in naive mice, their presence was dictated by antigen specificity and required IL-15.

Optimal protection against infection requires noncirculating memory.

While CD4 Th1 cells are required for resistance to intramacrophage infections, adoptive transfer of Th1 cells is insufficient to protect against infection. Using an epitope-tagged vaccine strain of , we found that effective protection correlated with expanded -specific memory CD4 T cells in circulation and nonlymphoid tissues. However, naive mice that previously shared a blood supply with vaccinated partners lacked T cell memory with characteristics of tissue residence and did not acquire robust protective immunity.

IFN Regulatory Factor 3 Balances Th1 and T Follicular Helper Immunity during Nonlethal Blood-Stage Infection.

Differentiation of CD4 Th cells is critical for immunity to malaria. Several innate immune signaling pathways have been implicated in the detection of blood-stage parasites, yet their influence over Th cell immunity remains unclear. In this study, we used reactive TCR transgenic CD4 T cells, termed PbTII cells, during nonlethal AS and 17XNL infection in mice, to examine Th cell development in vivo.

Development of a Novel CD4 TCR Transgenic Line That Reveals a Dominant Role for CD8 Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria.

We describe an MHC class II (I-A)-restricted TCR transgenic mouse line that produces CD4 T cells specific for species. This line, termed PbT-II, was derived from a CD4 T cell hybridoma generated to blood-stage ANKA (PbA). PbT-II cells responded to all species and stages tested so far, including rodent (PbA, NK65, AS, and 17XNL) and human () blood-stage parasites as well as irradiated PbA sporozoites.

Single-cell RNA-seq and computational analysis using temporal mixture modelling resolves Th1/Tfh fate bifurcation in malaria.

Differentiation of naïve CD4 T cells into functionally distinct T helper subsets is crucial for the orchestration of immune responses. Due to extensive heterogeneity and multiple overlapping transcriptional programs in differentiating T cell populations, this process has remained a challenge for systematic dissection . By using single-cell transcriptomics and computational analysis using a temporal mixtures of Gaussian processes model, termed GPfates, we reconstructed the developmental trajectories of Th1 and Tfh cells during blood-stage infection in mice.