Allogeneic T cell responses drive reactivity to foreign tissues in the setting of solid organ or hematopoietic stem cell transplantation (allo-HSCT). After allo-HSCT, donor alloreactive T cells induce both beneficial graft-versus-tumor activity and harmful graft-versus-host-disease, a life- threatening complication that limits the effectiveness of allo-HSCT. Graft-versus-host-disease is a serious medical problem for which existing therapeutic interventions are often ineffective. In addition, existing strategies to control graft-versus-host disease impair anti-tumor responses, leading to an increased risk of cancer relapse. Discovering novel immunomodulatory approaches to control the harmful effects of allogeneic T cell responses without eliminating their beneficial anti-cancer activity is essential to improve the long-term success and widespread applicability of allo-HSCT. We have identified a new critical role for Notch signaling in alloreactive T cells mediating graft-versus-host disease after allo-HSCT. Inhibition of canonical Notch signaling in donor T cells markedly reduced the severity and mortality of graft-versus-host disease in several mouse models of allo-HSCT. Notch-deprived T cells proliferated normally and showed increased expansion in lympho-hematopoietic organs, demonstrating the absence of global immunosuppression. Notably, Notch-deprived alloreactive T cells acquired efficient cytotoxicity in vivo and retained potent anti-leukemia activity, leading to markedly improved overall survival of the recipients. However, their ability to produce multiple inflammatory cytokines was reduced. Notch inhibition also decreased the accumulation of alloreactive T cells in the intestine, a key GVHD target organ. Thus, Notch signaling represents a promising therapeutic target to control graft-versus-host disease while preserving significant anti- cancer activity in donor T cells after allo-HSCT. We hypothesize that Notch is a new essential regulator of T cell function in allogeneic T cell responses. To explore this hypothesis in detail, we will determine the specific Notch ligands and receptors that mediate Notch activation in T cells after allogeneic HSCT;investigate the cellular and molecular mechanisms underlying the decreased induction of GVHD by Notch-deficient alloreactive T cells;and identify the cytotoxic pathways that mediate the persistent anti-cancer activity of CD4+ and CD8+ T cells upon Notch inhibition. These studies will bring novel insights into the molecular regulation of alloimmunity and might lead to the development of new approaches to limit damaging consequences of T cell reactivity after allogeneic transplantation. .
Allogeneic T cell responses against host antigens mediate graft-versus-host disease, the most serious complication of allogeneic hematopoietic stem cell transplantation. The goal of this proposal is to evaluate the role of Notch signaling in the regulation of T cell alloimmunity. Completion of this project will not only reveal novel functions of the Notch signaling pathway in the immune system, but also pave the way for therapeutic manipulation of Notch signaling in T cell-mediated disorders, including graft-versus-host disease, organ rejection and autoimmunity.
|Jones, Morgan; Osawa, Gail; Regal, Joshua A et al. (2014) Hematopoietic stem cells are acutely sensitive to Acd shelterin gene inactivation. J Clin Invest 124:353-66|
|Mukherjee, Sumanta; Rasky, Andrew J; Lundy, Phil A et al. (2014) STAT5-induced lunatic fringe during Th2 development alters delta-like 4-mediated Th2 cytokine production in respiratory syncytial virus-exacerbated airway allergic disease. J Immunol 192:996-1003|
|Radojcic, Vedran; Maillard, Ivan (2014) A jagged road to lymphoma aggressiveness. Cancer Cell 25:261-3|
|Tsai, Yu-Hwai; VanDussen, Kelli L; Sawey, Eric T et al. (2014) ADAM10 regulates Notch function in intestinal stem cells of mice. Gastroenterology 147:822-834.e13|
|Khoriaty, Rami; Vasievich, Matthew P; Jones, Morgan et al. (2014) Absence of a red blood cell phenotype in mice with hematopoietic deficiency of SEC23B. Mol Cell Biol 34:3721-34|
|Tran, Ivy T; Sandy, Ashley R; Carulli, Alexis J et al. (2013) Blockade of individual Notch ligands and receptors controls graft-versus-host disease. J Clin Invest 123:1590-604|
|Rakowski, Lesley A; Garagiola, Derek D; Li, Choi M et al. (2013) Convergence of the ZMIZ1 and NOTCH1 pathways at C-MYC in acute T lymphoblastic leukemias. Cancer Res 73:930-41|
|Sandy, Ashley R; Chung, Jooho; Toubai, Tomomi et al. (2013) T cell-specific notch inhibition blocks graft-versus-host disease by inducing a hyporesponsive program in alloreactive CD4+ and CD8+ T cells. J Immunol 190:5818-28|
|Sandy, Ashley R; Stoolman, Josh; Malott, Kelli et al. (2013) Notch signaling regulates T cell accumulation and function in the central nervous system during experimental autoimmune encephalomyelitis. J Immunol 191:1606-13|
|Ebens, Christen L; Maillard, Ivan (2013) Notch signaling in hematopoietic cell transplantation and T cell alloimmunity. Blood Rev 27:269-77|