Post-Transcriptional Regulation of Interleukin-7 Receptor Expression

Division Of Basic Sciences - Nci

Investigators

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Abstract

IL-7 receptor expression and signaling is ciritical for conventional T cells, but the role of IL-7 receptor in innate-like T cells is less well understood. Specifically, the IL-7 requirement for invariant NKT (iNKT) cells, which is a thymus-derived population of effector T cells that plays potent regulatory roles in inflammation and cancer, has remained unclear. We have recently expanded our studies from conventional ab T cells into the role of IL-7 in iNKT cells, and we documented a previously unappreciated requirement for IL-7 in iNKT cell homeostasis. The conventional view on iNKT cells has been that this T cell population is mostly dependent on IL-15 signaling for their survival and maintenance, and that IL-7 only plays a minor role in this process. Using IL-15-deficient mice and employing adult thymectomized mice that were implanted with either IL-7- or IL-15-releasing osmotic pumps, we now demonstrated that it is IL-7, and not IL-15, that controls the homeostasis of iNKT cells in peripheral tissues (Park JY et al., 2022, Cell Reports). These results establish a new requirement for IL-7R expression on mature iNKT cells, thus expanding the role of IL-7 in T cell biology. Whether other innate-like T cells, such as MAIT cells, PLZF+ gd T cells, and thymic innate CD8 T cells also require IL-7R expression and signaling for their homeostasis is not clear to us, but we aim to address these issues in our future studies. Along these lines, we have also assessed the role of IL-7 on ab T cells in non-lymphoid tissues, including the liver, lung, and the epithelium of the small intestine (SI). The SI intra-epithelial lymphocytes (IELs) correspond to the largest reservoir of T cells in the body, and they are considered to play critical roles in maintaining immune surveillance and quiescence in the gut. Here, we found that SI IELs differ in their cytokine requirement for survival, so that they are mostly independent of IL-7, and they also cannot respond to IL-7. The molecular basis of the IL-7-independent homeostasis of SI IEL T cells is currently a major question that we are addressing in this project, and we are testing the hypothesis that the SI epithelial microenvironment would be providing these survival cues. In this regard, we recently reported that Foxp3 Treg cells, which need IL-2 for their survival and effector function, are exempt from their IL-2 requirement once they enter the SI epithelium (Prakhar P. et al., 2021, JCI Insights). Collectively, these results indicated that the role and requirement for cytokines differ depending on the tissue, and that the tissue environment needs to be taken into account when assessing the individual role of a given cytokine. Finally, we have initiated a series of new studies on the regulatory mechanisms of IL-7 receptor expression where we also address the epigenetic aspect of IL-7R expression. Specifically, we are assessing a role for the chromatin remodeling zinc finger transcription factor Ikaros (Ikfz1) as a novel regulator of controlling the accessibility of IL-7Ra gene locus. As such, we found that Ikfz1 controls IL-7Ra expression during the early T cell development in the thymus and in the survival/homeostasis of peripheral T cells. To further understand how Ikaros contributes to cytokine receptor regulation in general, and specifically to IL-7Ra expression, we have generated a series of Ikfz1-conditional knock out mice whereby Ikfz1-floxed mice were crossed with CD2-Cre recombinase transgenic mice or CD4-Cre transgenic mice, among others. In parallel, we also generated Ikfz1 transgenic mice to test the effect of Ikfz1 overexpression on T cell generation and homeostasis in the context of IL-7R signaling. Analyzing the T cell development and differentiation of these mice in context of IL-7R expression is currently under investigation.