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.

Antigen-driven EGR2 expression is required for exhausted CD8 T cell stability and maintenance.

Chronic stimulation of CD8 T cells triggers exhaustion, a distinct differentiation state with diminished effector function. Exhausted cells exist in multiple differentiation states, from stem-like progenitors that are the key mediators of the response to checkpoint blockade, through to terminally exhausted cells. Due to its clinical relevance, there is substantial interest in defining the pathways that control differentiation and maintenance of these subsets.

The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8 T Cell Tolerance Checkpoint to High-Dose Antigen.

Escape from peripheral tolerance checkpoints that control cytotoxic CD8 T cells is important for cancer immunotherapy and autoimmunity, but pathways enforcing these checkpoints are mostly uncharted. We reveal that the HECT-type ubiquitin ligase activator, NDFIP1, enforces a cell-intrinsic CD8 T cell checkpoint that desensitizes TCR signaling during in vivo exposure to high antigen levels. Ndfip1-deficient OT-I CD8 T cells responding to high exogenous tolerogenic antigen doses that normally induce anergy aberrantly expanded and differentiated into effector cells that could precipitate autoimmune diabetes in RIP-OVA mice.

Effective Priming of Herpes Simplex Virus-Specific CD8 T Cells Does Not Require Infected Dendritic Cells.

Resolution of virus infections depends on the priming of virus-specific CD8 T cells by dendritic cells (DC). While this process requires major histocompatibility complex (MHC) class I-restricted antigen presentation by DC, the relative contribution to CD8 T cell priming by infected DC is less clear. We have addressed this question in the context of a peripheral infection with herpes simplex virus 1 (HSV).

Systems-guided forward genetic screen reveals a critical role of the replication stress response protein ETAA1 in T cell clonal expansion.

T-cell immunity requires extremely rapid clonal proliferation of rare, antigen-specific T lymphocytes to form effector cells. Here we identify a critical role for ETAA1 in this process by surveying random germ line mutations in mice using exome sequencing and bioinformatic annotation to prioritize mutations in genes of unknown function with potential effects on the immune system, followed by breeding to homozygosity and testing for immune system phenotypes. Effector CD8 and CD4 T-cell formation following immunization, lymphocytic choriomeningitis virus (LCMV) infection, or herpes simplex virus 1 (HSV1) infection was profoundly decreased despite normal immune cell development in adult mice homozygous for two different mutations: an exon 2 skipping allele that deletes Gly78-Leu119, and a Cys166Stop truncating allele that eliminates most of the 877-aa protein.

FOXO3 is differentially required for CD8 T-cell death during tolerance versus immunity.

Peripheral tolerance mechanisms limit autoimmunity by constitutively eliminating self-reactive CD8 T cells from the periphery in a process called deletion. Previous work has demonstrated that this deletion process is mediated by BIM-dependent apoptotic death due to transcriptional induction of the Bim gene. Currently, the transcriptional pathways responsible for Bim induction during peripheral deletion remain unclear.

Cerebral Vasculitis in X-linked Lymphoproliferative Disease Cured by Matched Unrelated Cord Blood Transplant.

Unlabelled: Vasculitis occurs rarely in association with X-linked lymphoproliferative disease (XLP). There are four published cases of non-EBV XLP-associated cerebral vasculitis reported, none of whom have survived without major cognitive impairment.

Case: A 9-year old boy initially presented aged 5 years with a restrictive joint disease.

The utility of an isolated mitochondrial fraction in the preparation of liposomes for the specific delivery of bioactives to mitochondria in live mammalian cells.

Purpose: To develop and evaluate liposomal formulations prepared with an isolated mitochondrial fraction as a mitochondria-specific delivery vehicle.

Methods: Liposomes were prepared with either a crude mitochondrial fraction extracted from cells or lipids extracted from the crude mitochondrial fraction and were then characterized by determining their size and zeta potential. The cell uptake of the liposomes and loaded bioactive was studied using flow cytometry and confocal microscopy.

Approaches for targeting mitochondria in cancer therapy.

The recognition of the role that mitochondria play in human health and disease is evidenced by the emergence in recent decades of a whole new field of "Mitochondrial Medicine". Molecules located on or inside mitochondria are considered prime pharmacological targets and a wide range of efforts are underway to exploit these targets to develop targeted therapies for various diseases including cancer. However the concept of targeting, while seemingly simple in theory, has multiple subtly different practical approaches.