Pregnancy induced displacement of preexisting microchimeric cells in the absence of maternal B and T cells.

Bidirectional exchange of cells between mother and fetus occurs during pregnancy, and persistence of these genetically foreign cells establishes long-term microchimerism in both individuals after parturition. Since women can have multiple pregnancies, and all mothers were once daughters themselves, the microchimeric milieu in each woman could theoretically contain cells from a variety of origins, including from their own mothers as well as their babies from each pregnancy. Interestingly and in sharp contrast to this prediction, we recently showed preexisting populations of microchimeric cells are lost following pregnancy and associated with seeding of new fetal microchimeric cells.

Microbiota-derived inosine programs protective CD8 T cell responses against influenza in newborns.

The immunological defects causing susceptibility to severe viral respiratory infections due to early-life dysbiosis remain ill-defined. Here, we show that influenza virus susceptibility in dysbiotic infant mice is caused by CD8 T cell hyporesponsiveness and diminished persistence as tissue-resident memory cells. We describe a previously unknown role for nuclear factor interleukin 3 (NFIL3) in repression of memory differentiation of CD8 T cells in dysbiotic mice involving epigenetic regulation of T cell factor 1 (TCF 1) expression.

Reproductive outcomes after pregnancy-induced displacement of preexisting microchimeric cells.

Pregnancy confers partner-specific protection against complications in future pregnancy that parallel persistence of fetal microchimeric cells (FMcs) in mothers after parturition. We show that preexisting FMcs become displaced by new FMcs during pregnancy and that FMc tonic stimulation is essential for expansion of protective fetal-specific forkhead box P3 (FOXP3)-positive regulatory T cells (T cells). Maternal microchimeric cells and accumulation of T cells with noninherited maternal antigen (NIMA) specificity are similarly overturned in daughters after pregnancy, highlighting a fixed microchimeric cell niche.

Maternal-fetal conflict averted by progesterone- induced FOXP3+ regulatory T cells.

Pregnancy stimulates an intricately coordinated assortment of physiological changes to accommodate growth of the developing fetus, while simultaneously averting rejection of genetically foreign fetal cells and tissues. Despite increasing evidence that expansion of immune-suppressive maternal regulatory T cells enforces fetal tolerance and protects against pregnancy complications, the pregnancy-associated signals driving this essential adaptation remain poorly understood. Here we show that the female reproductive hormone, progesterone, coordinates immune tolerance by stimulating expansion of FOXP3+ regulatory T cells.

Epidemiology of Pregnancy Complications Through the Lens of Immunological Memory.

In the fifteen minutes it takes to read this short commentary, more than 400 babies will have been born too early, another 300 expecting mothers will develop preeclampsia, and 75 unborn third trimester fetuses will have died in utero (stillbirth). Given the lack of meaningful progress in understanding the physiological changes that occur to allow a healthy, full term pregnancy, it is perhaps not surprising that effective therapies against these great obstetrical syndromes that include prematurity, preeclampsia, and stillbirth remain elusive. Meanwhile, pregnancy complications remain the leading cause of infant and childhood mortality under age five.

Preconceptual Priming Overrides Susceptibility to Escherichia coli Systemic Infection during Pregnancy.

Maternal sepsis is a leading cause of morbidity and mortality during pregnancy. is a primary cause of bacteremia in women and occurs more frequently during pregnancy. Several key outstanding questions remain regarding how to identify women at highest infection risk and how to boost immunity against infection during pregnancy.

In situ mapping identifies distinct vascular niches for myelopoiesis.

In contrast to nearly all other tissues, the anatomy of cell differentiation in the bone marrow remains unknown. This is owing to a lack of strategies for examining myelopoiesis-the differentiation of myeloid progenitors into a large variety of innate immune cells-in situ in the bone marrow. Such strategies are required to understand differentiation and lineage-commitment decisions, and to define how spatial organizing cues inform tissue function.

CD8 T Cell Functional Exhaustion Overrides Pregnancy-Induced Fetal Antigen Alloimmunization.

Pregnancy necessitates physiological exposure, and often re-exposure, to foreign fetal alloantigens. The consequences after pregnancy are highly varied, with evidence of both alloimmunization and expanded tolerance phenotypes. We show that pregnancy primes the accumulation of fetal-specific maternal CD8 T cells and their persistence as an activated memory pool after parturition.

Persistent Zika Virus Clinical Susceptibility despite Reduced Viral Burden in Mice with Expanded Virus-Specific CD8 T Cells Primed by Recombinant .

Vaccines against Zika virus (ZIKV) infection that target CD8 T cells are of considerable interest because Abs may enhance infection susceptibility. However, whether CD8 T cells are protective or promote susceptibility to clinical infection symptoms remains uncertain. To more precisely investigate ZIKV-specific CD8 T cells in isolation, we engineered a -based vector to express a single MHC class I-restricted immune dominant peptide, E294-302, from ZIKV envelope protein.

Regulation of bile duct epithelial injury by hepatic CD71+ erythroid cells.

Extramedullary hematopoietic cells are present in the liver of normal neonates in the first few days of life and persist in infants with biliary atresia. Based on a previous report that liver genes are enriched by erythroid pathways, we examined the liver gene expression pattern at diagnosis and found the top 5 enriched pathways are related to erythrocyte pathobiology in children who survived with the native liver beyond 2 years of age. Using immunostaining, anti-CD71 antibodies identified CD71+ erythroid cells among extramedullary hematopoietic cells in the livers at the time of diagnosis.

Commensal Candida albicans Positively Calibrates Systemic Th17 Immunological Responses.

Mucosal barriers are densely colonized by pathobiont microbes such as Candida albicans, capable of invasive disseminated infection. However, systemic infections occur infrequently in healthy individuals, suggesting that pathobiont commensalism may elicit host benefits. We show that intestinal colonization with C.

Enhanced survival following oral and systemic Salmonella enterica serovar Typhimurium infection in polymeric immunoglobulin receptor knockout mice.

Background: Polymeric immunoglobulin receptor (pIgR) transport of secretory immunoglobulin A (SIgA) to mucosal surfaces is thought to promote gut integrity and immunity to Salmonella enterica serovar Typhimurium (S. Typhimurium), an invasive pathogen in mice. To elucidate potential mechanisms, we assessed intestinal barrier function and both oral and systemic S.

l-Citrulline Metabolism in Mice Augments CD4 T Cell Proliferation and Cytokine Production , and Accumulation in the Mycobacteria-Infected Lung.

Activation, recruitment, and effector function of T lymphocytes are essential for control of mycobacterial infection. These processes are tightly regulated in T cells by the availability of l-arginine within the microenvironment. In turn, mycobacterial infection dampens T cell responsiveness through arginase induction in myeloid cells, promoting sequestration of l-arginine within the local milieu.

Commensal Fungi Recapitulate the Protective Benefits of Intestinal Bacteria.

Commensal intestinal microbes are collectively beneficial in preventing local tissue injury and augmenting systemic antimicrobial immunity. However, given the near-exclusive focus on bacterial species in establishing these protective benefits, the contributions of other types of commensal microbes remain poorly defined. Here, we show that commensal fungi can functionally replace intestinal bacteria by conferring protection against injury to mucosal tissues and positively calibrating the responsiveness of circulating immune cells.

Preconceptual Zika virus asymptomatic infection protects against secondary prenatal infection.

Pregnant women, and their fetal offspring, are uniquely susceptible to Zika virus and other microbial pathogens capable of congenital fetal infection. Unavoidable exposure to Zika virus in endemic areas underscores the need for identifying at-risk individuals, and protecting expecting mothers and their fetal offspring against prenatal infection. Here we show that primary Zika virus asymptomatic infection in mice confers protection against re-infection, and that these protective benefits are maintained during pregnancy.

Immunological implications of pregnancy-induced microchimerism.

Immunological identity is traditionally defined by genetically encoded antigens, with equal maternal and paternal contributions as a result of Mendelian inheritance. However, vertically transferred maternal cells also persist in individuals at very low levels throughout postnatal development. Reciprocally, mothers are seeded during pregnancy with genetically foreign fetal cells that persist long after parturition.

Programmed Death-1 Culls Peripheral Accumulation of High-Affinity Autoreactive CD4 T Cells to Protect against Autoimmunity.

Self-reactive CD4 T cells are incompletely deleted during thymic development, and their peripheral seeding highlights the need for additional safeguards to avert autoimmunity. Here, we show an essential role for the coinhibitory molecule programmed death-1 (PD-1) in silencing the activation of high-affinity autoreactive CD4 T cells. Each wave of self-reactive CD4 T cells that escapes thymic deletion autonomously upregulates PD-1 to maintain self-tolerance.

Offspring's Tolerance of Mother Goes Viral.

Pregnancy uniquely allows genetically discordant tissues of the mother and child to intimately coexist in harmony. In this issue of Immunity, Ou and colleagues show that hepatitis B virus exploits these naturally occurring immune tolerance pathways to establish persistent postnatal infection in offspring.

Tolerance to noninherited maternal antigens, reproductive microchimerism and regulatory T cell memory: 60 years after 'Evidence for actively acquired tolerance to Rh antigens'.

Compulsory exposure to genetically foreign maternal tissue imprints in offspring sustained tolerance to noninherited maternal antigens (NIMA). Immunological tolerance to NIMA was first described by Dr. Ray D.

Infection susceptibility and immune senescence with advancing age replicated in accelerated aging Lmna(Dhe) mice.

Aging confers increased susceptibility to common pathogens including influenza A virus. Despite shared vulnerability to infection with advancing age in humans and rodents, the relatively long time required for immune senescence to take hold practically restricts the use of naturally aged mice to investigate aging-induced immunological shifts. Here, we show accelerated aging Lmna(Dhe) mice with spontaneous mutation in the nuclear scaffolding protein, lamin A, replicate infection susceptibility, and substantial immune cell shifts that occur with advancing age.

Cross-Generational Reproductive Fitness Enforced by Microchimeric Maternal Cells.

Exposure to maternal tissue during in utero development imprints tolerance to immunologically foreign non-inherited maternal antigens (NIMA) that persists into adulthood. The biological advantage of this tolerance, conserved across mammalian species, remains unclear. Here, we show maternal cells that establish microchimerism in female offspring during development promote systemic accumulation of immune suppressive regulatory T cells (Tregs) with NIMA specificity.

CXCR3 blockade protects against Listeria monocytogenes infection-induced fetal wastage.

Mammalian pregnancy requires protection against immunological rejection of the developing fetus bearing discordant paternal antigens. Immune evasion in this developmental context entails silenced expression of chemoattractant proteins (chemokines), thereby preventing harmful immune cells from penetrating the maternal-fetal interface. Here, we demonstrate that fetal wastage triggered by prenatal Listeria monocytogenes infection is driven by placental recruitment of CXCL9-producing inflammatory neutrophils and macrophages that promote infiltration of fetal-specific T cells into the decidua.

Long-term repeated daily use of intragastric gavage hinders induction of oral tolerance to ovalbumin in mice.

Oral tolerance is dependent on the complex architecture of the mucosal system of the gastrointestinal tract, its associated lymphoid tissue, and specialized immune cells. Changes in this architecture or the failure of any of its components may hinder the generation of oral tolerance. The larynx and esophagus are the gateway to the gastrointestinal tract, serving as the site of oral antigen introduction to the immune system and may have an important role in establishing tolerance.

Perinatal Listeria monocytogenes susceptibility despite preconceptual priming and maintenance of pathogen-specific CD8(+) T cells during pregnancy.

Listeria monocytogenes (Lm) is an intracellular bacterium with unique predisposition for systemic maternal infection during pregnancy and morbid consequences for the developing fetus. Given the high mortality associated with prenatal Lm infection, strategies for augmenting protective immunity during the exceedingly vulnerable period of pregnancy are urgently needed. Herein, protection conferred by attenuated Lm administered before pregnancy against subsequent virulent Lm prenatal infection was evaluated.