We are studying the development and function of mucosal M cells and their role in immune surveillance. Our goal is to define the genes and mechanisms involved in the development and function of mucosal M cells. By identifying the critical steps and mechanisms in M cell biology, we will begin to establish their specific role in the mucosal immune response and its ability to mediate mucosal tolerance and the balance with commensal microbes. Our Working Hypothesis in these studies is that specific TNF Superfamily and TNF Receptor Superfamily genes along with coordinated expression of Jagged-1 mediate cellular interactions that specify M cell development and function. We will study two main steps in M cell development, defined by our studies on CD137- deficient mice. The first step is the commitment of M cell lineage progenitors from stem cells, which is dependent in part on ligands for the lymphotoxin ? receptors and the TNFa receptors. Expression of Jagged-1 by the established M cells may also inhibit generation of M cells from adjacent enterocytes. The second step, functional maturation of M cells, appears to be dependent on interactions between M cells and basolateral pocket B lymphocytes. Here, CD137 (TNFRSF9) and its ligand CD137L, may be an important signaling pair in this interaction.
Two specific aims examine these components of our hypothesis: (1) How is M cell lineage commitment and development regulated by Jagged-1/Notch interactions? (2) What are the specific CD137/CD137L cellular interactions regulating M cell basolateral pocket formation and M cell functional development? Regulation of the steady state numbers of M cells in the intestinal mucosa is a dynamic process, and the process depends on an active interplay between crypt stem cells, intestinal epithelium, and lymphocyte subpopulations. This process works in parallel among Peyer's patch, Isolated Lymphoid Follicles, and Villus M cells, and will be shaped by intestinal infection and inflammation (e.g., in Inflammatory Bowel Disease). Thus, a feedback loop exists where M cell transcytosis of lumenal microbes induces mucosal immune activation, which in turn drives production of new M cells. Our studies will provide important details on both the positive and negative regulators of this process.

Public Health Relevance

M cells are a specialized subset of epithelial cells overlying mucosal lymphoid tissues such as intestinal Peyer's patches;they have a unique selective particle transcytosis capability that enables particles as large as a few microns in diameter to cross the epithelial barrier. Thus, M cells play a central role in host-pathogen interactions. Curiously, while the host mucosal immune system relies on this transcytosis function to detect pathogens and induce protective secretory IgA immunity, many pathogenic viruses and bacteria also hijack M cell transcytosis to invade. This paradoxical dual role of M cells in infection and immunity becomes even more complex as infection- and autoimmune disease- induced inflammatory cytokines affect M cell differentiation. Regulation of the steady state numbers of M cells in the intestinal mucosa is a dynamic process, and the process depends on an active interplay between crypt stem cells, intestinal epithelium, and lymphocyte subpopulations. This process works in parallel among Peyer's patch, Isolated Lymphoid Follicles, and Villus M cells, and will be shaped by intestinal infection and inflammation (e.g., in Inflammatory Bowel Disease). Thus, a feedback loop exists where M cell transcytosis of lumenal microbes induces mucosal immune activation, which in turn drives production of new M cells. Our studies have identified a set of genes that appear to regulate M cell lineage commitment (Jagged-1, Notch) and functional development (CD137, CD137L) and interactions between M cells and associated B lymphocytes. The proposed project will provide important details on the role of these genes in both the positive and negative regulation of M cell development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI063426-07A1
Application #
8226561
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Rothermel, Annette L
Project Start
2004-12-01
Project End
2017-02-28
Budget Start
2012-03-02
Budget End
2013-02-28
Support Year
7
Fiscal Year
2012
Total Cost
$380,000
Indirect Cost
$130,000
Name
University of California Riverside
Department
None
Type
Schools of Medicine
DUNS #
627797426
City
Riverside
State
CA
Country
United States
Zip Code
92521
Bennett, Kaila M; Walker, Sharon L; Lo, David D (2014) Epithelial microvilli establish an electrostatic barrier to microbial adhesion. Infect Immun 82:2860-71
Hsieh, En-Hui; Lo, David D (2012) Jagged1 and Notch1 help edit M cell patterning in Peyer's patch follicle epithelium. Dev Comp Immunol 37:306-12
Lo, David D; Ling, Jun; Eckelhoefer, A Holly (2012) M cell targeting by a Claudin 4 targeting peptide can enhance mucosal IgA responses. BMC Biotechnol 12:7
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Wang, Jing; Gusti, Veronica; Saraswati, Andrea et al. (2011) Convergent and divergent development among M cell lineages in mouse mucosal epithelium. J Immunol 187:5277-85
Eckelhoefer, Holly A; Rajapaksa, Thejani E; Wang, Jing et al. (2011) Claudin-4: functional studies beyond the tight junction. Methods Mol Biol 762:115-28
Rajapaksa, Thejani E; Bennett, Kaila M; Hamer, Mary et al. (2010) Intranasal M cell uptake of nanoparticles is independently influenced by targeting ligands and buffer ionic strength. J Biol Chem 285:23739-46
Rajapaksa, Thejani E; Stover-Hamer, Mary; Fernandez, Xiomara et al. (2010) Claudin 4-targeted protein incorporated into PLGA nanoparticles can mediate M cell targeted delivery. J Control Release 142:196-205
Hsieh, En Hui; Fernandez, Xiomara; Wang, Jing et al. (2010) CD137 is required for M cell functional maturation but not lineage commitment. Am J Pathol 177:666-76

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