In utero human cytomegalovirus infection expands NK-like FcγRIII+ CD8+ T cells that mediate Fc antibody functions.

Human cytomegalovirus (HCMV) profoundly impacts host T and natural killer (NK) cells across the lifespan, yet how this common congenital infection modulates developing fetal immune cell compartments remains underexplored. Using cord blood from neonates with and without congenital HCMV (cCMV) infection, we identify an expansion of Fcγ receptor III (FcγRIII)-expressing CD8+ T cells following HCMV exposure in utero. Most FcγRIII+ CD8+ T cells express the canonical αβ T cell receptor (TCR) but a proportion express non-canonical γδ TCR.

An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation.

Introduction: High sustained anti-rhGAA antibody titers (HSAT; ≥12,800) are directly linked to reduced efficacy of enzyme replacement therapy (ERT) and subsequent clinical deterioration in infantile-onset Pompe disease (IOPD). We have previously demonstrated the safety and effectiveness of a bortezomib-based immune-tolerance induction (ITI) regimen (bortezomib, rituximab, methotrexate, and IVIG) in eliminating HSAT.

Methods: Here, we describe two IOPD cases (patients 6 and 8) who developed HSAT at 8 and 10 weeks on ERT despite transient low-dose methotrexate ITI administration in the ERT-naïve setting and were treated with a bortezomib-based ITI regimen, and we compare their courses to a series of six historical patients (patients 1-5, and 7) with a similar presentation who exemplify our evolving approach to treatment.

Immunophenotype associated with high sustained antibody titers against enzyme replacement therapy in infantile-onset Pompe disease.

Introduction: The efficacy of enzyme replacement therapy (ERT) with alglucosidase alfa for infantile-onset Pompe disease (IOPD) is limited in some patients due to the development of high and sustained antibody titers (HSAT; ≥12,800).

Methods: We carried out detailed immunophenotyping of IOPD patients (n=40), including analysis of circulating cell populations by flow cytometry and plasma cytokines by multiplex array, to determine whether patients with HSAT have unique immunological characteristics compared to those with low titers (LT; <12,800).

Results: Compared to patients with LT, patients who develop HSAT were skewed toward a type 2 immune profile, with an increased frequency of Th2 cells that was positively correlated with levels of Th2 (IL-4, IL-5, IL-13) and pro-inflammatory (IL-6, TNF-α, MIP-1α, MIP-1β) cytokines.

Homeostatic cytokines reciprocally modulate the emergence of prenatal effector PLZF+CD4+ T cells in humans.

The development of human prenatal adaptive immunity progresses faster than previously appreciated, with the emergence of memory CD4+ T cells alongside regulatory T cells by midgestation. We previously identified a prenatal specific population of promyelocytic leukemia zinc finger-positive (PLZF+) CD4+ T cells with heightened effector potential that were enriched in the developing intestine and accumulated in the cord blood of infants exposed to prenatal inflammation. However, the signals that drive their tissue distribution and effector maturation are unknown.

In utero human cytomegalovirus infection expands NK cell-like FcγRIII-expressing CD8+ T cells that mediate antibody-dependent functions.

Human cytomegalovirus (HCMV) profoundly modulates host T and natural killer (NK) cells across the lifespan, expanding unique effector cells bridging innate and adaptive immunity. Though HCMV is the most common congenital infection worldwide, how this ubiquitous herpesvirus impacts developing fetal T and NK cells remains unclear. Using computational flow cytometry and transcriptome profiling of cord blood from neonates with and without congenital HCMV (cCMV) infection, we identify major shifts in fetal cellular immunity marked by an expansion of Fcγ receptor III (FcγRIII)-expressing CD8+ T cells (FcRT) following HCMV exposure in utero.

Human fetal T cells: Insights into developmental specialization and mechanisms of lineage transition.

The switch from primitive to definitive hematopoiesis occurs early in development through the emergence of a wave of definitive hematopoietic stem cells from intraembryonic sites, supplanting the original primitive population of extraembryonically derived stem cells. When it became clear that unique features of the fetal immune system could not be reproduced by adult stem cells, it was hypothesized that a lineage of definitive fetal hematopoietic stem cells predominates antenatally, ultimately giving way to an emerging wave of adult stem cells and resulting in a "layered" fetal immune system consisting of overlapping lineages. It is now clear, however, that the transition from human fetal-to-adult T cell identity and function does not occur due to a binary switch between distinct fetal and adult lineages.

Understanding Early-Life Adaptive Immunity to Guide Interventions for Pediatric Health.

Infants are capable of mounting adaptive immune responses, but their ability to develop long-lasting immunity is limited. Understanding the particularities of the neonatal adaptive immune system is therefore critical to guide the design of immune-based interventions, including vaccines, in early life. In this review, we present a thorough summary of T cell, B cell, and humoral immunity in early life and discuss infant adaptive immune responses to pathogens and vaccines.

Single-Cell Mapping of Progressive Fetal-to-Adult Transition in Human Naive T Cells.

Whereas the human fetal immune system is poised to generate immune tolerance and suppress inflammation in utero, an adult-like immune system emerges to orchestrate anti-pathogen immune responses in post-natal life. It has been posited that cells of the adult immune system arise as a discrete ontological "layer" of hematopoietic stem-progenitor cells (HSPCs) and their progeny; evidence supporting this model in humans has, however, been inconclusive. Here, we combine bulk and single-cell transcriptional profiling of lymphoid cells, myeloid cells, and HSPCs from fetal, perinatal, and adult developmental stages to demonstrate that the fetal-to-adult transition occurs progressively along a continuum of maturity-with a substantial degree of inter-individual variation at the time of birth-rather than via a transition between discrete waves.

dittoSeq: universal user-friendly single-cell and bulk RNA sequencing visualization toolkit.

Summary: A visualization suite for major forms of bulk and single-cell RNAseq data in R. dittoSeq is color blindness-friendly by default, robustly documented to power ease-of-use and allows highly customizable generation of both daily-use and publication-quality figures.

Availability And Implementation: dittoSeq is an R package available through Bioconductor via an open source MIT license.

Helios enhances the preferential differentiation of human fetal CD4 naïve T cells into regulatory T cells.

T cell receptor (TCR) stimulation and cytokine cues drive the differentiation of CD4 naïve T cells into effector T cell populations with distinct proinflammatory or regulatory functions. Unlike adult naïve T cells, human fetal naïve CD4 T cells preferentially differentiate into FOXP3 regulatory T (T) cells upon TCR activation independent of exogenous cytokine signaling. This cell-intrinsic predisposition for T differentiation is implicated in the generation of tolerance in utero; however, the underlying mechanisms remain largely unknown.

Landscape of stimulation-responsive chromatin across diverse human immune cells.

A hallmark of the immune system is the interplay among specialized cell types transitioning between resting and stimulated states. The gene regulatory landscape of this dynamic system has not been fully characterized in human cells. Here we collected assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing data under resting and stimulated conditions for up to 32 immune cell populations.

CD161 contributes to prenatal immune suppression of IFNγ-producing PLZF+ T cells.

Background: While the human fetal immune system defaults to a program of tolerance, there is concurrent need for protective immunity to meet the antigenic challenges encountered after birth. Activation of T cells in utero is associated with the fetal inflammatory response with broad implications for the health of the fetus and of the pregnancy. However, the characteristics of the fetal effector T cells that contribute to this process are largely unknown.

In utero priming of highly functional effector T cell responses to human malaria.

Malaria remains a significant cause of morbidity and mortality worldwide, particularly in infants and children. Some studies have reported that exposure to malaria antigens in utero results in the development of tolerance, which could contribute to poor immunity to malaria in early life. However, the effector T cell response to pathogen-derived antigens encountered in utero, including malaria, has not been well characterized.

Lin28b Regulates Fetal Regulatory T Cell Differentiation through Modulation of TGF-β Signaling.

Immune tolerance between the fetus and mother represents an active process by which the developing fetus must not mount immune responses to noninherited Ags on chimeric maternal cells that reside in fetal tissue. This is, in part, mediated by the suppressive influence of CD4FOXP3CD25 regulatory T cells (Tregs). Fetal secondary lymphoid organs have an increased frequency of Tregs and, as compared with adult T cells, fetal naive CD4 T cells exhibit a strong predisposition to differentiate into Tregs when stimulated.

Levels of circulating myeloid subpopulations and of heme oxygenase-1 do not predict CD4(+) T cell recovery after the initiation of antiretroviral therapy for HIV disease.

The level (or frequency) of circulating monocyte subpopulations such as classical (CD14(hi)CD16(-)) and non-classical (CD14(dim)CD16(+)) monocytes varies during the course of HIV disease progression and antiretroviral therapy (ART). We hypothesized that such variation and/or differences in the degree to which these cells expressed the immunoregulatory enzyme, heme oxygenase-1 (HO-1), would be associated with CD4(+) T cell recovery after the initiation of ART. This hypothesis was tested in a cross-sectional study of four groups of HIV-infected subjects, including those who were seronegative, untreated virologic controllers [detectable viral load (VL) of <1000 copies/mL], untreated virologic non-controllers [VL > 10,000 copies/mL], and ART-mediated virologic controllers [VL < 75 copies/mL].

Distinct functional programming of human fetal and adult monocytes.

Preterm birth affects 1 out of 9 infants in the United States and is the leading cause of long-term neurologic handicap and infant mortality, accounting for 35% of all infant deaths in 2008. Although cytokines including interferon-γ (IFN-γ), interleukin-10 (IL-10), IL-6, and IL-1 are produced in response to in utero infection and are strongly associated with preterm labor, little is known about how human fetal immune cells respond to these cytokines. We demonstrate that fetal and adult CD14(+)CD16(-) classical monocytes are distinct in terms of basal transcriptional profiles and in phosphorylation of signal transducers and activators of transcription (STATs) in response to cytokines.

Fetal regulatory T cells and peripheral immune tolerance in utero: implications for development and disease.

The developing fetus must actively learn to tolerate benign antigens or suffer the consequences of broken tolerance. Tolerance of self-antigens prevents development of autoimmune diseases and is achieved by both deletion of autoreactive T cell clones in the thymus (central tolerance) and by the suppressive influence of CD4(+)  CD25(+)  FoxP3(+) regulatory T cells (Tregs) in the periphery. Fetal CD4(+) T cells have a strong predisposition to differentiate into tolerogenic Tregs that actively promote self-tolerance, as well as tolerance to non-inherited antigens on chimeric maternal cells that reside in fetal tissues.

Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans.

Although the mammalian immune system is generally thought to develop in a linear fashion, findings in avian and murine species argue instead for the developmentally ordered appearance (or "layering") of distinct hematopoietic stem cells (HSCs) that give rise to distinct lymphocyte lineages at different stages of development. Here we provide evidence of an analogous layered immune system in humans. Our results suggest that fetal and adult T cells are distinct populations that arise from different populations of HSCs that are present at different stages of development.

Naive human T cells are activated and proliferate in response to the heme oxygenase-1 inhibitor tin mesoporphyrin.

Heme oxygenase-1 (HO-1) and its catabolic by-products have potent anti-inflammatory activity in many models of disease. It is not known, however, if HO-1 also plays a role in the homeostatic control of T cell activation and proliferation. We demonstrate here that the HO-1 inhibitor tin mesoporphyrin (SnMP) induces activation, proliferation, and maturation of naive CD4(+) and CD8(+) T cells via interactions with CD14(+) monocytes in vitro.

Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero.

As the immune system develops, T cells are selected or regulated to become tolerant of self antigens and reactive against foreign antigens. In mice, the induction of such tolerance is thought to be attributable to the deletion of self-reactive cells. Here, we show that the human fetal immune system takes advantage of an additional mechanism: the generation of regulatory T cells (Tregs) that suppress fetal immune responses.

Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE epsilon4/epsilon4 genotype accelerates HIV disease progression.

Originally recognized for their role in lipoprotein metabolism and cardiovascular disease, apolipoprotein (apo) E isoforms (apoE2, apoE3, and apoE4) have also been implicated to play a key role in several biological processes not directly related to their lipid transport function. For example, apoE4 contributes significantly to neurodegeneration in Alzheimer's disease. However, the role of apoE in infectious diseases is less well defined.