The idea that the Notch receptor family might play a role in hematopoiesis was first suggested when an activated form of the receptor was noted in a rare subset of childhood acute lymphoblastic leukemia (ALL). Since that time Notch and its associated family of membrane-bound ligands have been implicated as key modulators of differentiation virtually throughout the hematopoietic cascade. Decision points influenced by Notch have been defined at the stem cell level with self-renewal versus differentiation, in the myeloid lineage with macrophage versus dendritic cell differentiation, and at multiple steps in lymphoid differentiation including T-versus B-cell commitment. Understanding how Notch affects individual steps in the complex sequence of T-cell differentiation requires isolating these events, separating them from cumulative preceding effects of Notch activation.
Garciía-Peydró and colleagues (page 2444) have provided new insight by doing just that, taking subsets of human thymocytes, transducing them with an activated form of the Notch1 receptor, and replacing them in an ex vivo thymic culture that permits further differentiation. They specifically studied the events occurring before antigen-mediated positive or negative selection. This interval in T-cell differentiation involves a complex series of steps with limited known external influences. Among these steps is whether the T-cell receptor ultimately expressed on the mature T cell will bear the dimeric alpha and beta chains or the gamma and delta chains, a choice that substantially impacts T-cell function. Garciía-Peydró et al demonstrate that Notch1 activation induces significant favoring of the gamma-delta T-cell receptors, skewing differentiation fate prior to antigen specification. Thus, Notch signaling is capable of strongly influencing T-cell outcome prior to an impact of antigenic context. By favoring the gamma-delta cell population, Notch increases a set of lymphocytes associated with antitumor immunity and autoimmune phenomena.
While these studies pose an additional potential role for Notch in the composition of the adaptive immune system, they leave open the question of whether and how Notch is activated in physiologic settings to influence immune function. There is now no question that Notch has T-cell differentiation stage-specific effects; a concept furthered by the elegant experiments of Garciía-Peydró et al. But how Notch ligands are expressed within the microenvironments in which T-cell differentiation is occurring, whether expression of these ligands is modulated, and whether thymocytes in vivo are responding to Notch ligand-mediated cues are yet to be fully elucidated. Armed with greater understanding of where in the differentiation process Notch may play a role, the spade work can now begin of defining just where interventions involving Notch-ligand interactions can make a difference and whether this is indeed a molecule to target for interventions in immunologic disease.
