For over a decade, inflammatory bowel disease (IBD) and other chronic inflammatory disorders including multiple sclerosis and rheumatoid arthritis have been described as Th1-mediated disorders because IFN3- producing CD4 T cells are prevalent in diseased patients and IFN3 strongly activates macrophages, potentiating inflammation. However recent data from animal models of numerous autoimmune/chronic inflammatory disorders suggests that a new lineage of effector CD4 T cells, the IL-17-producing Th17 cells, are responsible for the induction of disease. Interestingly, the onset of these chronic inflammatory diseases is associated with elevated numbers of both IFN3+ and IL-17+ effector CD4 T cells at the sites of inflammation, opening the debate on the individual roles of these effector CD4 T cell populations during disease. In fact, the impact of Th1 CD4 T cells on the development of IBD remains controversial. In certain models of colitis, IFN3 does not appear necessary for disease induction, yet it has been demonstrated that transfer of in vitro- polarized Th1 cells can elicit experimental colitis in mice. Importantly, Th1-associated transcription factors Tbet and STAT4 are required to induce experimental IBD, suggesting a possibly unrecognized role for Th1 effector CD4 T cells in mediating chronic inflammation independent of IFN3 secretion, as these transcription factors are not required for IL-17 production. We hypothesize that Th1 CD4 T cells function to induce IL- 23-dependent colitis in a Tbet-dependent, STAT4-dependent, and non-IFN3-dependent mechanism. We propose the following specific aims to test this hypothesis:
Aim 1. To determine the role of in vivo derived IFN3+ CD4 T cells during IL-23-dependent colitis.
Aim 2. To determine the prerequisite for Tbet in the CD4 T cell compartment during IBD.
Aim 3. To determine the requirement for STAT4 signaling in CD4 T cells during colitis. Collectively these studies are designed to provide new information regarding the cellular mediators of colitis and to precisely define the properties and molecular regulators which control the development of pathogenic CD4 T cells. These findings have the potential to identify new targets for therapeutic and preventative strategies designed to ablate inflammatory bowel disease.
Inflammatory bowel disease is the result of dysregulated CD4 T cell responses and it is not fully understood what CD4 T cells do to cause disease. By investigating the origin of the colitis-inducing of CD4 T cells and decipher the mechanisms by which they cause disease, we will learn novel information that may be beneficial for the development of possible therapies to alleviate inflammatory bowel diseases.
|Shin, Boyoung; Kress, Robert L; Kramer, Philip A et al. (2018) Effector CD4 T cells with progenitor potential mediate chronic intestinal inflammation. J Exp Med 215:1803-1812|
|Tian, Yuan; Mollo, Sarah B; Harrington, Laurie E et al. (2016) IL-10 Regulates Memory T Cell Development and the Balance between Th1 and Follicular Th Cell Responses during an Acute Viral Infection. J Immunol 197:1308-21|
|McWilliams, Ian L; Rajbhandari, Rajani; Nozell, Susan et al. (2015) STAT4 controls GM-CSF production by both Th1 and Th17 cells during EAE. J Neuroinflammation 12:128|
|Beurel, Eléonore; Harrington, Laurie E; Buchser, William et al. (2014) Astrocytes modulate the polarization of CD4+ T cells to Th1 cells. PLoS One 9:e86257|
|Liu, Yudong; Holdbrooks, Andrew T; De Sarno, Patrizia et al. (2014) Therapeutic efficacy of suppressing the Jak/STAT pathway in multiple models of experimental autoimmune encephalomyelitis. J Immunol 192:59-72|
|Yeh, Wen-I; McWilliams, Ian L; Harrington, Laurie E (2014) IFN? inhibits Th17 differentiation and function via Tbet-dependent and Tbet-independent mechanisms. J Neuroimmunol 267:20-7|
|Mollo, Sarah B; Ingram, Jennifer T; Kress, Robert L et al. (2014) Virus-specific CD4 and CD8 T cell responses in the absence of Th1-associated transcription factors. J Leukoc Biol 95:705-713|
|Beurel, Eléonore; Kaidanovich-Beilin, Oksana; Yeh, Wen-I et al. (2013) Regulation of Th1 cells and experimental autoimmune encephalomyelitis by glycogen synthase kinase-3. J Immunol 190:5000-11|
|Beurel, Eléonore; Harrington, Laurie E; Jope, Richard S (2013) Inflammatory T helper 17 cells promote depression-like behavior in mice. Biol Psychiatry 73:622-30|
|Mollo, Sarah B; Zajac, Allan J; Harrington, Laurie E (2013) Temporal requirements for B cells in the establishment of CD4 T cell memory. J Immunol 191:6052-9|
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