Inflammatory bowel disease is believed to result from an inappropriate immune response to commensal intestinal microbes in a genetically susceptible host. Aberrant sensing of microbes by the innate immune system triggers the development of pathogenic T lymphocytes that initiate and propagate intestinal inflammation. Recent evidence has suggested a novel role for an evolutionarily conserved mechanism called asymmetric cell division in regulating adaptive immune responses to microbes. During asymmetric division, segregation of cell fate determinants to one side of the plane of division enables their unequal inheritance and the divergence of daughter cell fates. We have previously shown that a T lymphocyte appears to undergo asymmetric division to give rise to two differentially fated daughter cells (J.T. Chang et al., Science 2007). We observed, moreover, that the conserved atypical PKC (aPKC)-Par3-Par6 and Scrib-Dlg-Lgl polarity complexes, which regulate polarity and asymmetric division in other model organisms, establish complementary domains within dividing T cells recruited into an immune response against a microbial pathogen. Preliminary evidence from our laboratory using an adoptive transfer model of colitis suggests that CD4+ T cells may undergo asymmetric division during a dysregulated immune response to commensal intestinal microbes. We hypothesize that the polarity network regulates asymmetric division in activated CD4+ T cells, influencing their differentiation into pathogenic, colitis-inducing cells. In this proposal, we will test the hypothesis that the aPKC and Scrib polarity complexes regulate the ability of CD4+ T lymphocytes to undergo asymmetric division, differentiate into pathogenic Th1 and Th17 effector cells, and mediate intestinal inflammation. Accomplishment of these aims is likely to yield important insights about fundamental mechanisms underlying the pathogenesis of IBD, and could identify new targets against which future therapies might be directed.

Public Health Relevance

In inflammatory bowel disease, cells of the immune system engage in an aberrant response against intestinal bacteria. This project will investigate the process by which certain immune cells, T lymphocytes, develop into the pathogenic cells that cause intestinal inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK093507-01A1
Application #
8302661
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
2012-04-01
Project End
2017-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$336,853
Indirect Cost
$119,353
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Kakaradov, Boyko; Arsenio, Janilyn; Widjaja, Christella E et al. (2017) Early transcriptional and epigenetic regulation of CD8+ T cell differentiation revealed by single-cell RNA sequencing. Nat Immunol 18:422-432
Bertin, Samuel; Aoki-Nonaka, Yukari; Lee, Jihyung et al. (2017) The TRPA1 ion channel is expressed in CD4+ T cells and restrains T-cell-mediated colitis through inhibition of TRPV1. Gut 66:1584-1596
Klann, Jane E; Remedios, Kelly A; Kim, Stephanie H et al. (2017) Talin Plays a Critical Role in the Maintenance of the Regulatory T Cell Pool. J Immunol 198:4639-4651
Metz, Patrick J; Lopez, Justine; Kim, Stephanie H et al. (2016) Regulation of Asymmetric Division by Atypical Protein Kinase C Influences Early Specification of CD8(+) T Lymphocyte Fates. Sci Rep 6:19182
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Ngoi, Soo M; Lopez, Justine M; Chang, John T (2016) The Microtubule-Associated Protein Lis1 Regulates T Lymphocyte Homeostasis and Differentiation. J Immunol 196:4237-45
Arsenio, Janilyn; Metz, Patrick J; Chang, John T (2015) Asymmetric Cell Division in T Lymphocyte Fate Diversification. Trends Immunol 36:670-683
Barrera, Daniel J; Rosenberg, Julian N; Chiu, Joanna G et al. (2015) Algal chloroplast produced camelid VH H antitoxins are capable of neutralizing botulinum neurotoxin. Plant Biotechnol J 13:117-24
Kamphuis, Lars G; Hane, James K; Nelson, Matthew N et al. (2015) Transcriptome sequencing of different narrow-leafed lupin tissue types provides a comprehensive uni-gene assembly and extensive gene-based molecular markers. Plant Biotechnol J 13:14-25
Metz, Patrick J; Arsenio, Janilyn; Kakaradov, Boyko et al. (2015) Regulation of asymmetric division and CD8+ T lymphocyte fate specification by protein kinase C? and protein kinase C?/?. J Immunol 194:2249-59

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