Interleukin-2 (IL-2/-/-) deficient transgenic mice regularly develop severe, persistent colitis, which resembles ulcerative colitis in humans. The selective inflammation of the colon suggests IL-2 plays a critical role in regulating mucosal immune responses. We have recently demonstrated that this disease is dependent on mature T, but not B lymphocytes. Thus, dysregulated T lymphocytes are likely to mediate colitis in both these mutant strains. Because IL-2 has previously been shown to program activated T cells to undergo programmed cell death, we postulated that the absence of IL-2/IL-2 alpha receptor signaling leads to a defect in programmed cell death (PCD) of activated T lymphocytes. Preliminary studies suggest that activation induced cell death (AICD) is indeed compromised in both these strains. As AICD is important for the normal regulation of the duration of immune responses, this defect may allow activated mucosal T cells to cause persistent colonic inflammation. In this application, we propose to confirm and extend our preliminary findings defining the role of T cells in mediating colitis in these animals, compare the propensity of mucosal and systemic lymphocytes from IL-2 - - mice to undergo PCD, and study the expression of proteins known to regulate PCD. These studies should not only lead to a better understanding of how IL-2 regulates mucosal immune responses, but may also lead to important insights into the pathogenesis of human IBD.
| Boone, David L; Turer, Emre E; Lee, Eric G et al. (2004) The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol 5:1052-60 |
| Boone, David L; Dassopoulos, Themistocles; Chai, Sophia et al. (2003) Fas is not essential for lamina propria T lymphocyte homeostasis. Am J Physiol Gastrointest Liver Physiol 285:G382-8 |
| Boone, David L; Lee, Eric G; Libby, Shon et al. (2002) Recent advances in understanding NF-kappaB regulation. Inflamm Bowel Dis 8:201-12 |
| Boone, David L; Dassopoulos, Themistocles; Lodolce, James P et al. (2002) Interleukin-2-deficient mice develop colitis in the absence of CD28 costimulation. Inflamm Bowel Dis 8:35-42 |
| Lodolce, James; Burkett, Patrick; Koka, Rima et al. (2002) Interleukin-15 and the regulation of lymphoid homeostasis. Mol Immunol 39:537-44 |
| Lodolce, J P; Burkett, P R; Boone, D L et al. (2001) T cell-independent interleukin 15Ralpha signals are required for bystander proliferation. J Exp Med 194:1187-94 |
| Lodolce, J P; Boone, D L; Chai, S et al. (1998) IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 9:669-76 |
