Effective effector generation of CD8⁺ T cells and NK cells: A need for T-bet and ZEB-too

Insight from Sara Hamilton (left) and Stephen Jameson (right)

Both T cells and NK cells employ complex networks of transcriptional regulators to control their differentiation and functional prowess. In this issue, three studies report that the transcription factor ZEB2 is critical for generation and expansion of terminally differentiated effector cells, chiefly by working in partnership with T-bet.

Several transcription factors have been shown to regulate CD8⁺ T cell differentiation during an immune response. T-bet has emerged as a driving force in the development of KLRG1^hi terminal effector cells. Both Dominguez et al. and Omilusik et al. show here that ZEB2, a molecule not previously associated with lymphocyte differentiation, is strongly up-regulated in early KLRG1^hi effector cells and supports their progression to a short-lived effector status—yet appears dispensable for generation of long-lived memory cells. T-bet is required for ZEB2 expression, and the factors coregulate many of the same genes. However, the impact of ZEB2 deficiency could not be completely overcome by T-bet overexpression, and both cooperative and independent activities of these factors may be important.

It takes Zeb2 to tango: Cooperation between T-bet and Zeb2 is essential for CD8⁺ T cell effector differentiation and NK cell development. Although increasing T-bet expression alone can mediate some of the necessary gene expression changes, coordination with Zeb2 (which is itself under T-bet transcriptional control) is required for full commitment and expansion of terminally differentiated CD8⁺ T cells and mature NK cells.

Interestingly, van Helden et al. demonstrate a parallel role for ZEB2 in permitting NK cell maturation. Zeb2 deficiency thwarted normal NK cell differentiation, migration into peripheral tissues, and control of melanoma growth. Again, many of these features echo the role of T-bet in NK cell development, and there was ample evidence of cooperation between the factors in controlling gene expression; however, ZEB2 was not completely subservient to T-bet because ZEB2 could partially restore NK development in T-bet gene–deficient mice.

These studies characterize ZEB2 as a novel player in the transcriptional control of lymphocyte differentiation, playing strikingly similar roles in CD8⁺ T cells and NK cells. Numerous phenotypic and functional changes accompany the differentiation of lymphocytes—a challenge has been to understand how these differentiation states relate to complex transcriptional networks within the cell and how generation of a stable subset is achieved. ZEB2 is downstream of T-bet, but cooperation between these factors is crucial for regulation of multiple genes—hence ZEB2 may serve to reinforce the differentiation program initiated by T-bet expression. However, whereas both ZEB2 and T-bet inhibit expression of memory precursor-associated genes in CD8⁺ T cells, Dominguez, et al. suggest that low level ZEB2 expression is required for generation of the CD8⁺ T cell effector-memory subset, indicating a more nuanced role. Also, whereas ZEB2 does not appear necessary for acquisition of key effector functions (such as cytolysis and IFN-γ production) by terminally differentiated CD8⁺ T cells or mature NK cells, it will be important to see how this factor impacts pathogen control in various contexts. Deciphering the pathways that promote effector cell generation may help direct strategies for better vaccine approaches, and understanding the cooperative and independent roles of T-bet and Zeb2 could provide new targets for therapeutic intervention.