CD1d-restricted, invariant natural killer T cells (iNKT) cells play a critical role in regulating the commensal microbiota and resistance to mucosal pathogens. Conversely, iNKT cell levels are suppressed by microbiota in early (pre-weaned), but not later (post-weaned), life. If critical microbial signals are not provided during early life, colonic iNKT cell levels remain elevated leading to increased susceptibility to colitis in later-life. Recently, we discovered that colon iNKT cells are resident cells that establish themselves in early life in a pathway controlled locally by macrophages within a developmental program regulated by specific microbial factors. The current research proposal addresses the unanswered question about how macrophages and thiazole-oxazole modified microcins (TOMMs) associated with Escherichia coli regulate intestinal iNKT cells in early life. Our long-term goals are to parse out specific mechanisms and consequences of host-microbial interactions in regulating intes- tinal iNKT cells and in turn how iNKT cells regulate commensalism, pathogenic exposures and colitis. The ob- jective of this research is to better understand the pathways that regulate iNKT cells in early life. Our central hypothesis is that intestinal iNKT cells are resident cells established in early life and under the control of macro- phages and specific microbial factors which determines later life susceptibility to enteric diseases. Specifically, it is proposed that microbes regulate embryonic macrophages in colon which determines the colonic receptivity to early life entry and proliferation of thymic iNKT cell emigrants through cognate and non-cognate mechanisms. We also hypothesize that E. coli expressing TOMMs determine a unique form of colonization resistance in early life that involves impeding iNKT cell residency. The rationale for our proposed research is that developing such insights and the consequences they have for later life susceptibility to enteric diseases will have important impli- cations for processes associated with colonization resistance and immune tolerance. Our central hypothesis will be tested with three specific aims: 1) define the role of fetal macrophages in early life regulation of colon iNKT cell residency; 2) define the sources and mechanisms of the cognate signals that regulate establishment of CD1d-restricted iNKT cell residency, and; 3) define bacterial-derived oxazoles as a regulator of early life iNKT cell development in intestines.
In Aim 1 we will show how iNKT cells establish residency in the colon in early life through the activities of embryonic macrophages and the role played by the commensal microbiota.
Aim 2 will investigate how CD1d on intestinal macrophages regulate local iNKT cell levels during this critical period of development. Finally, Aim 3 will reveal how a specific microbial factor derived from TOMMs regulate intestinal iNKT cell levels and their control of commensalism in early life. Overall, this proposal is significant because it will demonstrate that iNKT cells are resident cells that are under the control of a developmental process which is regulated and in turn regulates the microbiota and as such provides new opportunities for potentially manipulat- ing these processes in a preventative manner.
The proposed research is relevant to public health because it will reveal specific details about how microbes and the host interact during a critical developmental period of early life to determine iNKT cell levels and sus- ceptibility or resistance to enteric diseases. Such information is of potential importance to diseases of the esophagus (e.g. eosinophilic esophagitis), small intestine (e.g. celiac disease) and colon (e.g. infections, can- cer and inflammatory bowel disease) where iNKT cells have been shown to play a role. The proposed studies are relevant to the mission of the NIDDK because they will identify new mechanisms by which the host and microbes interact in determining tissue tolerance and colonization resistance as well as provide specific in- sights into ways in which such information can be used to prevent and potentially treat mucosal conditions that depend upon iNKT cells.
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| Schrumpf, Elisabeth; Jiang, Xiaojun; Zeissig, Sebastian et al. (2017) The role of natural killer T cells in a mouse model with spontaneous bile duct inflammation. Physiol Rep 5: |
| Tschurtschenthaler, Markus; Adolph, Timon E; Ashcroft, Jonathan W et al. (2017) Defective ATG16L1-mediated removal of IRE1? drives Crohn's disease-like ileitis. J Exp Med 214:401-422 |
| Kaser, Arthur; Blumberg, Richard S (2017) The road to Crohn's disease. Science 357:976-977 |
| Zeissig, Sebastian; Peuker, Kenneth; Iyer, Shankar et al. (2017) CD1d-Restricted pathways in hepatocytes control local natural killer T cell homeostasis and hepatic inflammation. Proc Natl Acad Sci U S A 114:10449-10454 |
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