Intrathymic IL-7: the where, when, and why of IL-7 signaling during T cell development

Abstract

The thymus is the birthplace of all T lineage cells. But the thymus is also a cradle as it provides the environment for further maturation and differentiation of immature thymocytes. While many factors contribute to make the thymus a unique place for T cell development, here we review the essential role of intrathymic interleukin-7 (IL-7). In the absence of IL-7 signaling, survival, proliferation and differentiation of immature thymocytes are all severely impaired. Consequently, IL-7 is critical to nurture and guide T precursor cells through the diverse steps of thymic maturation. Interestingly, even as IL-7 signaling is such a critical factor, IL-7 signaling must be also actively suppressed during specific stages of T cell differentiation. These contradictory observations are puzzling but can be satisfactorily explained when understanding the developmental context of IL-7 signaling. In this regard, here we will discuss the spatiotemporal expression of intrathymic IL-7 and address the stage-specific effects of IL-7 signaling in developing thymocytes. Specifically, we will review other facets of intrathymic IL-7 beyond its role as a pro-survival factor and so clarify and reaffirm the unique role of IL-7 as a prime factor in T cell development and differentiation.

Figure 1. IL-7 receptor expression and IL-7 signaling during T cell development in the thymus

T cell development starts with the entry of early thymic progenitor cells (ETP) through the cortico-medullary junction (CMJ) followed by their migration towards the subcapsular zone. IL-7Rα expression is initiated during this migratory phase, specifically in DN2 stage cells, which is critical for IL-7 dependent survival and proliferation of TCRβ-selected thymocytes. Upon further differentiation into DN4 and DP cells, IL-7Rα expression is terminated. DP thymocytes then reside in an IL-7 poor environment refractory to IL-7 signaling and pre-programmed to cell death. It is only after TCR-mediated positive selection that IL-7Rα expression is re-induced and that these cells become IL-7 signaling competent. Persistent TCR signaling desensitizes IL-7 signaling and permits CD4 lineage differentiation. Cessation of TCR signaling, however, allows IL-7R signaling in intermediate cells, and it is intrathymic IL-7 signaling that imposes CD8 lineage specification during CD4/CD8 lineage choice in the thymus.