Using mass spectrometry to identify neoantigens in autoimmune diseases: The type 1 diabetes example.

In autoimmune diseases, recognition of self-antigens presented by major histocompatibility complex (MHC) molecules elicits unexpected attack of tissue by autoantibodies and/or autoreactive T cells. Post-translational modification (PTM) may alter the MHC-binding motif or TCR contact residues in a peptide antigen, transforming the tolerance to self to autoreactivity. Mass spectrometry-based immunopeptidomics provides a valuable mechanism for identifying MHC ligands that contain PTMs and can thus provide valuable insights into pathogenesis and therapeutics of autoimmune diseases.

IL-15 enhances HIV-1 infection by promoting survival and proliferation of CCR5+CD4+ T cells.

HIV-1 usually utilizes CCR5 as its coreceptor and rarely switches to a CXCR4-tropic virus until the late stage of infection. CCR5+CD4+ T cells are the major virus-producing cells in viremic individuals as well as SIV-infected nonhuman primates. The differentiation of CCR5+CD4+ T cells is associated with the availability of IL-15, which increases during acute HIV-1 infection.

B-1 plasma cells require non-cognate CD4 T cell help to generate a unique repertoire of natural IgM.

Evolutionarily conserved, "natural" (n)IgM is broadly reactive to both self and foreign antigens. Its selective deficiency leads to increases in autoimmune diseases and infections. In mice, nIgM is secreted independent of microbial exposure to bone marrow (BM) and spleen B-1 cell-derived plasma cells (B-1PC), generating the majority of nIgM, or by B-1 cells that remain non-terminally differentiated (B-1sec).

TCR-engineered adoptive cell therapy effectively treats intracranial murine glioblastoma.

Background: Adoptive cellular therapies with chimeric antigen receptor T cells have revolutionized the treatment of some malignancies but have shown limited efficacy in solid tumors such as glioblastoma and face a scarcity of safe therapeutic targets. As an alternative, T cell receptor (TCR)-engineered cellular therapy against tumor-specific neoantigens has generated significant excitement, but there exist no preclinical systems to rigorously model this approach in glioblastoma.

Methods: We employed single-cell PCR to isolate a TCR specific for the Imp3 neoantigen (mImp3) previously identified within the murine glioblastoma model GL261.

Profiling the peripheral immune response to ex vivo TNF stimulation in untreated juvenile idiopathic arthritis using single cell RNA sequencing.

Background: Juvenile Idiopathic Arthritis (JIA) is an autoimmune disease with a heterogenous clinical presentation and unpredictable response to available therapies. This personalized transcriptomics study sought proof-of-concept for single-cell RNA sequencing to characterize patient-specific immune profiles.

Methods: Whole blood samples from six untreated children, newly diagnosed with JIA, and two healthy controls were cultured for 24 h with or without ex vivo TNF stimulation and subjected to scRNAseq to examine cellular populations and transcript expression in PBMCs.

Persons with HIV Develop Spike-Specific Lymph Node Germinal Center Responses following SARS-CoV-2 Vaccination.

COVID-19 disproportionately affects persons with HIV (PWH) in worldwide locations with limited access to SARS-CoV-2 vaccines. PWH exhibit impaired immune responses to some, but not all, vaccines. Lymph node (LN) biopsies from PWH demonstrate abnormal LN structure, including dysregulated germinal center (GC) architecture.

Accumulation of TCR signaling from self-antigens in naive CD8 T cells mitigates early responsiveness.

The cumulative effects of T cell receptor (TCR) signal transduction over extended periods of time influences T cell biology, such as the positive selection of immature thymocytes or the proliferative responses of naive T cells. Naive T cells experience recurrent TCR signaling in response to self-antigens in the steady state. However, how these signals influence the responsiveness of naive CD8 T cells to subsequent agonist TCR stimulation remains incompletely understood.

Corrigendum: Intraocular human cytomegaloviruses of ocular diseases are distinct from those of viremia and are capable of escaping from innate and adaptive immunity by exploiting HLA-E-mediated peripheral and central tolerance.

[This corrects the article DOI: 10.3389/fimmu.2022.

Sex and prior exposure jointly shape innate immune responses to a live herpesvirus vaccine.

Background: Both sex and prior exposure to pathogens are known to influence responses to immune challenges, but their combined effects are not well established in humans, particularly in early innate responses critical for shaping subsequent outcomes.

Methods: We employed systems immunology approaches to study responses to a replication-defective, herpes simplex virus (HSV) 2 vaccine in men and women either naive or previously exposed to HSV.

Results: Blood transcriptomic and cell population profiling showed substantial changes on day 1 after vaccination, but the responses depended on sex and whether the vaccinee was naive or previously exposed to HSV.

Entry receptors - the gateway to alphavirus infection.

Alphaviruses are enveloped, insect-transmitted, positive-sense RNA viruses that infect humans and other animals and cause a range of clinical manifestations, including arthritis, musculoskeletal disease, meningitis, encephalitis, and death. Over the past four years, aided by CRISPR/Cas9-based genetic screening approaches, intensive research efforts have focused on identifying entry receptors for alphaviruses to better understand the basis for cellular and species tropism. Herein, we review approaches to alphavirus receptor identification and how these were used for discovery.

Immunomodulatory effects of colchicine on peripheral blood mononuclear cell subpopulations in human obesity: Data from a randomized controlled trial.

Objective: Colchicine is known to reduce inflammation and improve endothelial cell function and atherosclerosis in obesity, but there is little knowledge of the specific circulating leukocyte populations that are modulated by colchicine.

Methods: A secondary analysis of a double-blind randomized controlled trial of colchicine 0.6 mg or placebo twice daily for 3 months on circulating leukocyte populations and regulation of the immune secretome in 35 adults with obesity was performed.

SARS-CoV-2 booster vaccination rescues attenuated IgG1 memory B cell response in primary antibody deficiency patients.

Background: Although SARS-CoV-2 vaccines have proven effective in eliciting a protective immune response in healthy individuals, their ability to induce a durable immune response in immunocompromised individuals remains poorly understood. Primary antibody deficiency (PAD) syndromes are among the most common primary immunodeficiency disorders in adults and are characterized by hypogammaglobulinemia and impaired ability to mount robust antibody responses following infection or vaccination.

Methods: Here, we present an analysis of both the B and T cell response in a prospective cohort of 30 individuals with PAD up to 150 days following initial COVID-19 vaccination and 150 days post mRNA booster vaccination.

Influenza vaccination reveals sex dimorphic imprints of prior mild COVID-19.

Acute viral infections can have durable functional impacts on the immune system long after recovery, but how they affect homeostatic immune states and responses to future perturbations remain poorly understood. Here we use systems immunology approaches, including longitudinal multimodal single-cell analysis (surface proteins, transcriptome and V(D)J sequences) to comparatively assess baseline immune statuses and responses to influenza vaccination in 33 healthy individuals after recovery from mild, non-hospitalized COVID-19 (mean, 151 days after diagnosis) and 40 age- and sex-matched control individuals who had never had COVID-19. At the baseline and independent of time after COVID-19, recoverees had elevated T cell activation signatures and lower expression of innate immune genes including Toll-like receptors in monocytes.

DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression.

Myeloproliferative neoplasms (MPNs) exhibit a propensity for transformation to secondary acute myeloid leukemia (sAML), for which the underlying mechanisms remain poorly understood, resulting in limited treatment options and dismal clinical outcomes. Here, we performed single-cell RNA sequencing on serial MPN and sAML patient stem and progenitor cells, identifying aberrantly increased expression of DUSP6 underlying disease transformation. Pharmacologic dual-specificity phosphatase (DUSP)6 targeting led to inhibition of S6 and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling while also reducing inflammatory cytokine production.

The phosphatidylinositol-transfer protein Nir3 promotes PI(4,5)P replenishment in response to TCR signaling during T cell development and survival.

Hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP) by phospholipase C-γ (PLCγ1) represents a critical step in T cell antigen receptor (TCR) signaling and subsequent thymocyte and T cell responses. PIP replenishment following its depletion in the plasma membrane (PM) is dependent on delivery of its precursor phosphatidylinositol (PI) from the endoplasmic reticulum (ER) to the PM. We show that a PI transfer protein (PITP), Nir3 (Pitpnm2), promotes PIP replenishment following TCR stimulation and is important for T cell development.

Clinical Determinants of Childhood Onset Systemic Lupus Erythematosus among Early and Peri-Adolescent Age Groups.

Introduction: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that is associated with significant morbidity and mortality. SLE disproportionately affects women and minorities. Childhood-onset SLE (cSLE) in particular tends to be more aggressive than adult-onset SLE.

Adaptive immune responses to SARS-CoV-2 persist in the pharyngeal lymphoid tissue of children.

Most studies of adaptive immunity to SARS-CoV-2 infection focus on peripheral blood, which may not fully reflect immune responses at the site of infection. Using samples from 110 children undergoing tonsillectomy and adenoidectomy during the COVID-19 pandemic, we identified 24 samples with evidence of previous SARS-CoV-2 infection, including neutralizing antibodies in serum and SARS-CoV-2-specific germinal center and memory B cells in the tonsils and adenoids. Single-cell B cell receptor (BCR) sequencing indicated virus-specific BCRs were class-switched and somatically hypermutated, with overlapping clones in the two tissues.