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.

Soluble γc cytokine receptor suppresses IL-15 signaling and impairs iNKT cell development in the thymus

“…Thus, the physiological role of sγc proteins can be wide-ranging and diverse. Here we assessed the effect of sγc expression on thymic development, and we show that increased sγc production results in impaired thymopoiesis, which is a process dependent on IL-7 signaling3, and also in diminished i NKT cell generation, which is an event dependent on IL-15 signaling72139. Generation of IL-2-dependent Foxp3 + Treg cells or IL-7-dependent CD8SP thymocytes51041, on the other hand, were not affected.…”

“…Among others, IL-7 is essential for thymopoiesis23, IL-2 is necessary for Foxp3 + Treg cell development45, and IL-15 is required for the development of invariant NKT ( i NKT) cells in the thymus67. Notably, γc cytokine responsiveness is mostly acquired during or after initiation of lineage-specification during thymocyte development.…”

“…Notably, γc cytokine responsiveness is mostly acquired during or after initiation of lineage-specification during thymocyte development. As such, pre-selection CD4 + CD8 + double-positive (DP) thymocytes are unresponsive to IL-789, and IL-7 responsiveness is acquired upon cessation of positive selection signals in post-selection CD4 or CD8 single-positive (SP) thymocytes31011. DP thymocytes are also unresponsive to IL-2, and IL-2 responsiveness in CD4 thymocytes is only acquired by strong TCR engagements that also upregulate expression of the transcription factor Foxp31213.…”

Thymus transcriptome reveals novel pathways in response to avian pathogenic Escherichia coli infection

“…Moreover, IL7 exerts a significant impact on naive T-cell survival, proliferation, and homeostasis in mammals (Hsu and Mountz, 2010; Vicente et al., 2010; Hong et al., 2012). Hsu and Mountz (2010) reported that the interaction between IL7 and IL7R could lead to proliferation and progression of T cells.…”

IL-7/anti–IL-7 mAb complexes augment cytokine potency in mice through association with IgG-Fc and by competition with IL-7R

“…[1][2][3][4][5] Among its pleiotropic effects, IL-7 determines the overall size of the resting T-cell pool as the prototypic survival factor for T cells. 6 In lymphoid tissues, stromal cells constitutively produce the IL-7 relevant to T-cell homeostasis, and IL-7 levels are thought to be controlled through consumption by IL-7 receptor (IL-7R)-expressing cells.…”