Autoreactive CD4 and CD8 T cells and large numbers of B220+ CD4-CD8-double negative (DN) (( T cells accumulate in mice with impaired Fas-mediated apoptosis leading to autoimmune lymphoproliferation. Similar autoimmune disease (ALPS) occurs in humans with impaired Fas pathway. Paradoxically, T cell lymphoproliferation associated with loss of function in the Fas pathway does not result in overt T cell-mediated autoimmunity. Impairment of the Fas pathway even confers resistance to autoimmune diabetes in mice. Neither the function of B220+ DN T cells, nor the mechanism by which the autoreactive T cells in affected are controlled is clearly understood. We have examined and found that B220+ DN T cells are immunoregulatory T cells that suppress polyclonal and antigen specific T cell activation in vitro and prevent T cell-mediated colitis in an animal model of inflammatory bowel disease. In normal animals, B220+ DN T cells are found in the appendix and large intestine. We hypothesize that B220+ DN T cells are important for maintenance of mucosal and peripheral tolerance. We propose two specific aims to investigate this hypothesis: 1) To understanding the molecular mechanism of B220+ DN T cell-mediated suppression, we will use DNA microarray assay and in vitro and in vivo functional studies to identify genes whose products are involved in mediating B220+ DN T cell suppressor function. 2) To define the role of B220+ DN T cells in systemic and mucosal tolerance, we will analyze whether neonatal transfer of B220+ DN T cells prevents a) the fatal lymphoproliferation in scurfy mice or b) enterocolitis in IL-10 deficient mice. The findings generated by these studies will aid in characterizing a novel naturally occurring regulatory T cells and define their role in peripheral and mucosal tolerance. ? ?
| Hamad, Abdel Rahim A (2010) Analysis of gene profile, steady state proliferation and apoptosis of double-negative T cells in the periphery and gut epithelium provides new insights into the biological functions of the Fas pathway. Immunol Res 47:134-42 |
| Mohamood, Abdiaziz S; Bargatze, Dylan; Xiao, Zuoxiang et al. (2008) Fas-mediated apoptosis regulates the composition of peripheral alphabeta T cell repertoire by constitutively purging out double negative T cells. PLoS One 3:e3465 |
| Mohamood, Abdiaziz S; Guler, Mehmet L; Xiao, Zuoxiang et al. (2007) Protection from autoimmune diabetes and T-cell lymphoproliferation induced by FasL mutation are differentially regulated and can be uncoupled pharmacologically. Am J Pathol 171:97-106 |
| Mohamood, Abdiaziz S; Trujillo, Crystal J; Zheng, Dongfeng et al. (2006) Gld mutation of Fas ligand increases the frequency and up-regulates cell survival genes in CD25+CD4+ TR cells. Int Immunol 18:1265-77 |
