The Notch signaling pathway is known to play a pivotal role in T- and B-cell development and fate, presenting it as an attractive therapeutic target in alloimmunity. This review provides an overview of the mechanisms of Notch signaling, focusing on new insights into its diverse functions in T-cell activation, differentiation and memory subset formation, and the consequences thereof in transplantation.
Recent evidence has shown that while not critical for early antigen-specific CD4+ T-cell activation, Notch signaling regulates the survival of memory CD4+ T cells via control of glycolytic metabolism; in contrast, Notch signaling is critical for the generation of short-lived CD8+ effector T cells, but not memory CD8+ cells. Transient, selective inhibition of various Notch receptors and ligands in models of solid organ transplantation has been shown to successfully modulate the alloimmune response, affecting the balance between effector and regulatory cells, with particular influence on the natural regulatory T-cell population.
These studies reveal diverse roles for individual Notch receptors and ligands in peripheral immunity and indicate that selective targeting of the Notch pathway is a promising, novel approach for immune modulation in transplantation; the advent of therapeutic human antibodies to neutralize both the Notch ligands and the individual Notch receptors suggests that this approach could be efficiently developed.
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aSchuster Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
bDepartment of Renal Medicine and Transplantation, UCL Centre for Nephrology, Royal Free Hospital, London, UK
Correspondence to Leonardo V. Riella, MD, PhD, Schuster Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave, Boston MA 02115, USA. Tel: +1 617 732 5252; fax: +1 617 732 5254; e-mail: firstname.lastname@example.org
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