Ontogeny of the early life Immune system

The early life mammalian immune system has evolved to develop in functional layers. Innate and adaptive cell subsets with suppressive activity as well as potent pro-inflammatory activity may be found at various tissue sites in the fetus and in the newborn. In this arm of my lab’s research program, we study the role of two genes, RXRA and IGF2BP3 in the development of resident tissue macrophages and neonatal T cells respectively.

  • RXRA and resident tissue macrophages

    Resident tissue macrophages (RTMs) are a heterogeneous population of immune cells that fulfill numerous tissue- and niche-specific functions. RTMs develop from distinct waves of fetal progenitor cells that seed tissues before birth. Environment-specific signals including cytokines and metabolites drive a differentiation program that leads to the development and functional specialization of RTMs.

    In this project, we are investigating the role of the gene Rxra (Retinoid X receptor-alpha) in the development of RTMs. RXR⍺ is a ligand-dependent nuclear receptor that can heterodimerize with the retinoic acid receptor (RAR), the vitamin D Receptor (VDR) and PPARg, placing it squarely in the Vitamin A, D, and fatty acid signaling pathways respectively. Using a combination of genetic approaches and multi-dimensional flow cytometry and tissue imaging, we are investigating the function of RXRA in RTM development and function.

  • IGF2BP3 and early life T cell development

    Neonatal and adult T cells have different origins and functions. Unlike adult T cells, subsets of neonatal T cells are derived from fetal hematopoietic stem cells. Distinct pools of HSCs with diverging potential for generating T cell subsets colonize the thymus through ontogeny. The immediate postnatal period is thus represented by a mix of fetal and postnatally derived T cells with diverse functionality. One goal is to understand the genetic programs underlying these developmental transitions.

    We identified the gene Igf2bp3 to be highly expressed in early life. The immediate goals of this project are to determine the function of IGF2BP3 in early life T cell development. Our long-term goal is to elaborate the contribution of immune cells derived from distinct stages of ontogeny to overall immunity. Leveraging a combination of technologies, we will explore early life immunity with a new perspective.

Microbial Influence of Early Life Immunity

There is increasing evidence for an early-life time window when microbial encounters impact the development of select immune phenotypes. Three windows of influential microbial encounters may be distinguished in the pre- and post-natal period: microbial exposure in utero during pregnancy, microbes acquired at the time of delivery and microbes established postnatally by the acquisition of maternal and environmental bacteria. Thus, the first 1000 days of life, that is, the period from conception to 2 years of age, may provide opportunities for microbial imprint of immunity that could set thresholds of immune reactivity throughout life. When and how microbial inputs are interpreted in distinct early life environments may alter the nature of developmental immune layering, impact long-term immune function and drive hypersensitivity.  

A major focus of the lab’s research is understanding the impact of microbes on the development of early life immunity. This research is divided into 2 main programs investigating the contribution of commensal microbes and the role of maternal infection on offspring/early-life immunity.

  • Microbes and PLZF-expressing ILEs

    Innate lymphoid effectors cells or ILEs are fast acting immune effectors that mediate a spectrum of immune responses ranging from establishment of commensalism with microbes to the maintenance and repair of barrier surfaces. In previous work from our lab we showed that ILEs expressing the transcription factor PLZF, are particularly sensitive to intestinal microbial influence in early life. Importantly, early life ‘imprinting’ of PLZF-expressing ILEs by microbes influenced the susceptibility of adult animals to experimental colitis. PLZF+ ILEs are a heterogeneous mix of cells that include innate-like T cells as well as innate lymphoid cell (ILC) subsets that do not express antigen specific receptors but mirror effector T cells in their function and development. The main objective of this study is to identify the specific PLZF+ ILE subset that operates at barrier surfaces and regulates mucosal tolerance in both animal models and in patients with intestinal inflammation.

  • Microbes and maternal microchimeric cells

    Susceptibility (or resistance) to infection in infants is influenced by the maternal immunological experience. Chronic infection during pregnancy can affect infant health independently of pathogen transmission. Vertically transferred maternal antibodies including cross-placental maternal IgG and breastmilk IgA, provide high levels of pathogen-specific protection at birth. Maternal programming of offspring immunity may also take the form of vertically transmitted maternal cells. Acquired maternal cells (maternal microchimeric cells; MMCs) are retained in offspring for long periods of time and are proposed to have both beneficial and harmful roles. The role of acquired MMCs in maternal infection and subsequent neonatal immune responses remains unclear. One arm of the lab’s research program addresses this knowledge gaps. We have generated novel tools to study this phenomenon in mice.

PUBLICATIONS

HIGHLIGHTS

The early life education of the immune system: Moms, microbes and (missed) opportunities. Gut Microbes. 2020 2020 Oct 12;1-20.doi: 10.1080/19490976.2020.1824564.

Of Opportunities Missed and Taken

Early life microbial exposures influence developmental imprinting of the immune system that determines health and disease susceptibility in later life. Favorable imprinting of developing immunity by microbes may occur during an early life time window of opportunity. This window of opportunity, by definition, is predicted to be relatively short, to not arise again in later life and must provide a health benefit to the offspring. Numerous factors during pregnancy and in the postnatal period influence the quality of microbial exposures that have the potential to imprint immune functionality. Treatments and behaviors that disrupt these exposures may lead to pathological imprinting, altering risk for disease throughout life.

Intestinal microbes influence development of thymic lymphocytes in early life. Proc Natl Acad Sci U S A. (2020) Feb 4;117(5):2570-2578. doi: 10.1073/pnas.1915047117. Epub 2020 Jan 21.

Early Life Entero-thymic Communication

The early life represents a period of unique immune development during which the foundation for lifelong immunity is laid. Microbial exposures during early life have the potential to influence the development and functionality of immune cells that can have consequences on diseases susceptibility in later life. In this study, we demonstrate an early life entero-thymic communication where intestinal microbes impinge on the thymic development of transcription factor PLZF expressing innate lymphoid effector cells (ILEs). These ILEs typically function at the gut mucosal interface and provide protection at barrier sites. Offspring of animals treated with broad-spectrum antibiotics or those reared in a germfree environment had altered development of thymic ILEs. This early life microbial imprint on PLZF+ ILEs persisted into adulthood and contributed to their increased susceptibility to colitis. Protection from colitis could be initiated by the transfer of PLZF+ cells from mice that developed with normal microbiota in early life. These studies provide proof of concept for the regulation of immune development by intestinal microbes and affirm the existence of a ‘window of opportunity’ that may be exploited to program long-lasting host protective immune responses. 

Collaborators