Significance IL-15 is a cytokine critical for development and maintenance of T lymphoid cells. However, the identity and distribution of IL-15–expressing cells in lymphoid organs are not well understood. The present study reveals, by using IL-15–CFP knock-in mice that IL-15 was expressed in subsets of thymic epithelial cells, bone marrow stromal cells, lymph node stromal cells, and blood endothelial cells, a unique perspective of IL-15 niche in immune microenvironment. Taken together with our previous observation on IL-7–producing cells, this study suggests that some stromal cells express IL-7 and IL-15 differentially. Thus, the immune microenvironment appears to be consisted of functionally distinct subsets of stromal cells, expressing different cytokines.

Interleukin (IL)-7 is a cytokine essential for T lymphocyte development and homeostasis. However, little is known about the roles of IL-7 receptor α-chain (IL-7Rα) in late stages of T-cell development. To address this question, we established IL-7Rα-floxed mice and crossed them with CD4-Cre transgenic mice. Resultant IL-7R conditional knockout (IL-7RcKO) mice exhibited marked reduction in CD8 single positive (SP) T cells, regulatory T cells (Tregs), and natural killer T (NKT) cells in thymus. The proportion and proliferation of both mature CD4SP and CD8SP thymocytes were decreased without affecting Runx expression. In addition, expression of the glucocorticoid-induced TNF receptor was reduced in CD4SP and CD8SP thymocytes, and expression of CD5 was decreased in CD8SP thymocytes. IL-7RcKO mice also showed impaired Treg and NKT cell proliferation and inhibition of NKT cell maturation. Bcl-2 expression was reduced in CD4SP and CD8SP thymocytes but not in Tregs and NKT cells, and introduction of a Bcl-2 transgene rescued frequency and CD5 expression of CD8SP thymocytes. Furthermore, IL-7RcKO mice exhibited greatly increased numbers of B cells and, to a lesser extent, γδ T and dendritic cells in thymus. Overall, this study demonstrates that IL-7Rα differentially controls development and maturation of thymocyte subpopulations in late developmental stages and suggests that IL-7R expression on αβ T cells suppresses development of other cell lineages in thymus.differentiation | survival

IL-7 is a cytokine essential for T cell development and survival. However, the local function of IL-7 produced by thymic epithelial cells (TECs) is poorly understood. To address this question, we generated IL-7–floxed mice and crossed them with FoxN1 promoter–driven Cre (FoxN1-Cre) mice to establish knockout mice conditionally deficient for the expression of IL-7 by TECs. We found that αβ and γδ T cells were significantly reduced in the thymus of IL-7f/f FoxN1-Cre mice. Proportion of mature single-positive thymocytes was increased. In lymph nodes and the spleen, the numbers of T cells were partially restored in IL-7f/f FoxN1-Cre mice. In addition, γδ T cells were absent from the fetal thymus and epidermis of IL-7f/f FoxN1-Cre mice. Furthermore, TCRγδ+ intraepithelial lymphocytes (IELs) were significantly decreased in the small intestines of IL-7f/f FoxN1-Cre mice. To evaluate the function of IL-7 produced in the intestine, we crossed the IL-7f/f mice with villin promoter–driven Cre (Vil-Cre) mice to obtain the mice deficient in IL-7 production from intestinal epithelial cells. We observed that αβ and γδ IELs of IL-7f/f Vil-Cre mice were comparable to control mice. Collectively, our results suggest that TEC-derived IL-7 plays a major role in proliferation, survival, and maturation of thymocytes and is indispensable for γδ T cell development. This study also demonstrates that IL-7 produced in the thymus is essential for the development of γδ IELs and indicates the thymic origin of γδ IELs.

It is now well established that the E and Id protein axis regulates multiple steps in lymphocyte development. However, it remains unknown how E and Id proteins mechanistically enforce and maintain the naïve T-cell fate. Here we show that Id2 and Id3 suppressed the development and expansion of innate variant follicular helper T (T FH ) cells. Innate variant T FH cells required major histocompatibility complex (MHC) class I-like signaling and were associated with germinal center B cells. We found that Id2 and Id3 induced Foxo1 and Foxp1 expression to antagonize the activation of a T FH transcription signature. We show that Id2 and Id3 acted upstream of the Hif1a/ Foxo/AKT/mTORC1 pathway as well as the c-myc/p19Arf module to control cellular expansion. We found that mice depleted for Id2 and Id3 expression developed colitis and ab T-cell lymphomas. Lymphomas depleted for Id2 and Id3 expression displayed elevated levels of c-myc, whereas p19Arf abundance declined. Transcription signatures of Id2-and Id3-depleted lymphomas revealed similarities to genetic deficiencies associated with Burkitt lymphoma. We propose that, in response to antigen receptor and/or cytokine signaling, the E-Id protein axis modulates the activities of the PI3K-AKT-mTORC1-Hif1a and c-myc/p19Arf pathways to control cellular expansion and homeostatic proliferation.

The liver contains a variety of resident immune cells, such as NK cells, NKT cells, T cells, macrophages, and dendritic cells. However, little is known about how IL-7, which is produced by hepatocytes, functions locally in development and maintenance of liver immune cells. To address this question, we established IL-7–floxed mice and crossed them with albumin promoter-driven Cre (Alb-Cre) transgenic mice to establish conditional knockout of IL-7 in hepatocytes. The levels of IL-7 transcripts were reduced 10-fold in hepatocyte fraction. We found that the absolute numbers of NKT and T cells were significantly decreased in adult liver of IL-7f/f Alb-Cre mice compared with IL-7f/f control mice. In contrast, NK cells, dendritic cells, and B cells were unchanged in the IL-7f/f Alb-Cre liver. The number of Vα14+ invariant NKT cells was significantly reduced in liver, but not in thymus and spleen, of IL-7f/f Alb-Cre mice. Furthermore, B cell development was impaired in perinatal liver of IL-7f/f Alb-Cre mice. This study demonstrates that hepatocyte-derived IL-7 plays an indispensable role in maintenance of NKT and T cells in adult liver and development of B cells in fetal liver, and suggests that hepatocytes provide a unique IL-7 niche for intrahepatic lymphocytes.