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. We have previously shown that a T lymphocyte responding against a microbial pathogen appears to undergo asymmetric division to give rise to two differentially fated daughter cells (Chang et al., Science 2007). We have also recently provided evidence for a novel mechanism of asymmetric division whereby asymmetric localization of the proteasome, and consequently unequal degradation of factors targeted for destruction during mitosis, yields unequal partitioning of a key fate determinant to daughter cells (Chang et al., Immunity, in press). 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. In this proposal, we will: (1) determine whether asymmetric segregation of the proteasome is evident in dividing CD4+ T cells undergoing a dysregulated immune response to commensal microbes;and (2) determine whether inhibition of proteasome activity disrupts the ability of CD4+ T cells to cause intestinal inflammation. Accomplishment of the aims of this proposal may yield important insights into a novel mechanism that may regulate the pathogenesis of inflammatory bowel disease, and may identify a new pathway against which therapies could be directed.
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.
