The CD8 T cell tolerance checkpoint triggers a distinct differentiation state defined by protein translation defects.

Peripheral CD8 T cell tolerance is a checkpoint in both autoimmune disease and anti-cancer immunity. Despite its importance, the relationship between tolerance-induced states and other CD8 T cell differentiation states remains unclear. Using flow cytometric phenotyping, single-cell RNA sequencing (scRNA-seq), and chromatin accessibility profiling, we demonstrated that in vivo peripheral tolerance to a self-antigen triggered a fundamentally distinct differentiation state separate from exhaustion, memory, and functional effector cells but analogous to cells defectively primed against tumors.

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.

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 .

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.

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.

IL-1α promotes liver inflammation and necrosis during blood-stage Plasmodium chabaudi malaria.

Malaria causes hepatic inflammation and damage, which contribute to disease severity. The pro-inflammatory cytokine interleukin (IL)-1α is released by non-hematopoietic or hematopoietic cells during liver injury. This study established the role of IL-1α in the liver pathology caused by blood-stage P.

P2X7 receptor drives Th1 cell differentiation and controls the follicular helper T cell population to protect against Plasmodium chabaudi malaria.

A complete understanding of the mechanisms underlying the acquisition of protective immunity is crucial to improve vaccine strategies to eradicate malaria. However, it is still unclear whether recognition of damage signals influences the immune response to Plasmodium infection. Adenosine triphosphate (ATP) accumulates in infected erythrocytes and is released into the extracellular milieu through ion channels in the erythrocyte membrane or upon erythrocyte rupture.

Trachoma in Indigenous Settlements in Brazil, 2000-2008.

Purpose: Trachoma, caused by the bacterium Chlamydia trachomatis, is a chronic, recurrent inflammatory disease that affects the cornea and conjunctiva. Trachoma is the leading infectious cause of avoidable blindness worldwide. Its prevalence is higher among individuals of low socioeconomic status, and trachoma is common in indigenous communities.

In vivo approaches reveal a key role for DCs in CD4+ T cell activation and parasite clearance during the acute phase of experimental blood-stage malaria.

Dendritic cells (DCs) are phagocytes that are highly specialized for antigen presentation. Heterogeneous populations of macrophages and DCs form a phagocyte network inside the red pulp (RP) of the spleen, which is a major site for the control of blood-borne infections such as malaria. However, the dynamics of splenic DCs during Plasmodium infections are poorly understood, limiting our knowledge regarding their protective role in malaria.

Evaluation of naphthoquinones identified the acetylated isolapachol as a potent and selective antiplasmodium agent.

This study reports on the design, synthesis and antiparasitic activity of three new semi-synthetic naphthoquinones structurally related to the naturally-occurring lapachol and lapachone. Of the compounds tested, 3-(3-methylbut-1-en-1-yl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl acetate (1) was the most active against Plasmodium falciparum among both natural and semi-synthetic naphthoquinones, showing potent and selective activity. Compound 1 was able to reduce the in vitro parasite burden, in vitro parasite cell cycle, as well as the blood parasitemia in Plasmodium berghei-infected mice.

Antimalarial activity of physalins B, D, F, and G.

The antimalarial activities of physalins B, D, F, and G (1-4), isolated from Physalis angulata, were investigated. In silico analysis using the similarity ensemble approach (SEA) database predicted the antimalarial activity of each of these compounds, which were shown using an in vitro assay against Plasmodium falciparum. However, treatment of P.

The role of endoscopic treatment in the management of grade v primary vesicoureteral reflux.

Objectives: Although endoscopic treatment provides a high rate of success in children with grades II-IV vesicoureteral reflux (VUR), its role in the management of grade V reflux has been questioned. In this study we reviewed our 21-yr experience of endoscopic treatment in children with grade V primary VUR.

Methods: We retrospectively reviewed the medical records of 132 children who underwent endoscopic treatment for primary grade V reflux from 1984 to 2004.