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Embryonic macrophages function during early life to determine invariant natural killer T cell levels at barrier surfaces.

ABSTRACT: It is increasingly recognized that immune development within mucosal tissues is under the control of environmental factors during early life. However, the cellular mechanisms that underlie such temporally and regionally restrictive governance of these processes are unclear. Here, we uncover an extrathymic pathway of immune development within the colon that is controlled by embryonic but not bone marrow-derived macrophages, which determines the ability of these organs to receive invariant natural killer T (iNKT) cells and allow them to establish local residency. Consequently, early-life perturbations of fetal-derived macrophages result in persistent decreases of mucosal iNKT cells and is associated with later-life susceptibility or resistance to iNKT cell-associated mucosal disorders. These studies uncover a host developmental program orchestrated by ontogenically distinct macrophages that is regulated by microbiota, and they reveal an important postnatal function of macrophages that emerge in fetal life.

SUBMITTER: Gensollen T

PROVIDER: S-EPMC8171892 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Macrophages of embryonic origin function during early life to determine host iNKT cell levels at barrier surfaces

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Macrophages of embryonic origin function during early life to determine host iNKT cell levels at barrier surfaces III

Project description:It is increasingly recognized that immune development within mucosal tissues is under the control of environmental factors during early life. However, the cellular mechanisms that underlie such temporally and regionally restrictive governance of these processes is unclear. Here, we uncover an extrathymic pathway of immune development within the colon that is controlled by embryonic, but not bone-marrow derived, macrophages which determines the ability of these organs to receive invariant natural killer T (iNKT) cells and allow them to establish local residency. Consequently, early life perturbations of fetal-derived macrophages result in persistent decreases of mucosal iNKT cells and is associated with later life susceptibility or resistance to iNKT cell associated mucosal disorders. These studies uncover a host developmental program orchestrated by ontogenically distinct macrophages that is regulated by microbiota and reveal an important post-natal function of macrophages that emerge in fetal life.

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Macrophages of embryonic origin function during early life to determine host iNKT cell levels at barrier surfaces

Project description:Macrophages of embryonic origin function during early life to determine host iNKT cell levels at barrier surfaces

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Macrophages of embryonic origin function during early life to determine host iNKT cell levels at barrier surfaces I

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Macrophages of embryonic origin function during early life to determine host iNKT cell levels at barrier surfaces III

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Invariant natural killer T cells act as an extravascular cytotoxic barrier for joint-invading Lyme Borrelia.

Project description:CXCR6-GFP(+) cells, which encompass 70% invariant natural killer T cells (iNKT cells), have been found primarily patrolling inside blood vessels in the liver. Although the iNKT cells fail to interact with live pathogens, they do respond to bacterial glycolipids presented by CD1d on liver macrophage that have caught the microbe. In contrast, in this study using dual laser multichannel spinning-disk intravital microscopy of joints, the CXCR6-GFP, which also made up 60-70% iNKT cells, were not found in the vasculature but rather closely apposed to and surrounding the outside of blood vessels, and to a lesser extent throughout the extravascular space. These iNKT cells also differed in behavior, responding rapidly and directly to joint-homing pathogens like Borrelia burgdorferi, which causes Lyme disease. These iNKT cells interacted with B. burgdorferi at the vessel wall and disrupted dissemination attempts by these microbes into joints. Successful penetrance of B. burgdorferi out of the vasculature and into the joint tissue was met by a lethal attack by extravascular iNKT cells through a granzyme-dependent pathway, an observation also made in vitro for iNKT cells from joint but not liver or spleen. These results suggest a novel, critical extravascular iNKT cell immune surveillance in joints that functions as a cytotoxic barrier and explains a large increase in pathogen burden of B. burgdorferi in the joint of iNKT cell-deficient mice, and perhaps the greater susceptibility of humans to this pathogen because of fewer iNKT cells in human joints.

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