The age of an individual is an important, independent risk factor for many of the most common diseases afflicting modern societies. Interleukin-7 (IL-7) plays a central, critical role in the homeostasis of the immune system. Recent studies support a critical role for IL-7 in the maintenance of a vigorous healthspan. We describe the role of IL-7 and its receptor in immunosenescence, the aging of the immune system. An understanding of the role that IL-7 plays in aging may permit parsimonious preventative or therapeutic solutions for diverse conditions. Perhaps IL-7 might be used to "tune" the immune system to optimize human healthspan and longevity.

We have demonstrated that intestinal epithelial cells produce interleukin 7 (IL-7), and IL-7 serves as a potent regulatory factor for proliferation of intestinal mucosal lymphocytes expressing functional IL-7 receptor. To clarify the mechanism by which locally produced IL-7 regulates the mucosal lymphocytes, we investigated IL-7 transgenic mice. Here we report that transgenic mice expressing murine IL-7 cDNA driver by the SRalpha promoter developed chronic colitis in concert with the expression of SRalpha/IL-7 transgene in the colonic mucosa. IL-7 transgenic but not littermate mice developed chronic colitis at 4-12 wk of age, with histopathological similarity to ulcerative colitis in humans. Southern blot hybridization and competitive PCR demonstrated that the expression of IL-7 messenger RNA was increased in the colonic mucosal lymphocytes but not in the colonic epithelial cells. IL-7 protein accumulation was decreased in the goblet cell-depleted colonic epithelium in the transgenic mice. Immunohistochemical and cytokine production analysis showed that lymphoid infiltrates in the lamina propria were dominated by T helper cell type 1 CD4+ T cells. Flow cytometric analysis demonstrated that CD4+ intraepithelial T cells were increased, but T cell receptor gamma/delta T cells and CD8alpha/alpha cells were not increased in the area of chronic inflammation. Increased IL-7 receptor expression in mucosal lymphocytes was demonstrated in the transgenic mice. These findings suggest that chronic inflammation in the colonic mucosa may be mediated by dysregulation of colonic epithelial cell-derived IL-7, and this murine model of chronic colitis may contribute to the understanding of the pathogenesis of human inflammatory bowel disease.

IL-7 and IL-7Ralpha (IL-7R) form a non-redundant ligand receptor system which plays a crucial role in human T cell immunity. Both IL-7 and IL-7R are multi-exonal genes and exhibit alternative splicing. We measured the relative distribution of IL-7 and IL-7R spliced mRNA from patients with MS and healthy individuals and observed extensive alternative splicing of both genes with marked differences in proportional transcript expression levels. We report here for the first time that the IL-7 transcript, lacking exon 4, and not the full length IL-7 represents the dominant IL-7 RNA transcript in human PBMCs and a novel IL-7R splice variant lacking exons 5, 6 and 7.

Thymus implantation is a recently FDA-approved therapy for congenital athymia. Patients receiving thymus implantation develop a functional but incomplete T cell compartment. Our objective was to develop a mouse model to study clinical thymus implantation in congenital athymia and to optimise implantation procedures to maximise T cell education and expansion of naïve T cells.

Methods of identifying chronic wounds that will heal in a timely, coordinated fashion and those that will not, together with novel therapeutic strategies, are vital for progression in the field of wound healing. Interleukin (IL)-7 has been associated with various biological and pathological processes. The present study explored the potential role of IL-7 in wound healing. IL-7 expression levels were examined in a clinical cohort of chronic wounds using reverse transcription-quantitative polymerase chain reaction and immunohistochemical staining analysis. The impact of recombinant human IL-7 (rhIL-7) on the growth and migrational rates of HaCaT keratinocyte cells was subsequently examined using in vitro growth and electric cell-substrate impedance sensing functional assays. The mRNA expression levels of IL-7 were increased in the healed chronic wound tissue samples, compared with non-healed chronic wound tissue samples, although the difference was not statistically significant. Similarly, immunohistochemical analysis revealed a greater staining intensity of IL-7 in the healed chronic wound tissue sections compared with the non-healed tissue sections. Treatment with rhIL-7 did not affect HaCaT cell growth rates, but was shown to enhance cell migration, an effect that could be further enhanced through the addition of inhibitors of neuronal Wiskott-Aldrich syndrome protein and protein kinase B. The data of the present study suggest that the expression levels of IL-7 may be increased in healing chronic wounds, and thus IL-7 may have a role in this process, potentially through its effects on the cellular migration of keratinocytes.

Abnormal expression of inflammatory cytokines in major depressive disorder (MDD) suggests the activation of an inflammatory process. The pattern of alterations in cytokine levels is still ambiguous. The present study aimed to evaluate interleukin-7 (IL-7) and interleukin-10 (IL-10) for their involvement in the pathophysiology of MDD and determine their relationships with depression risk.

To investigate the potential synergy of IL-7-driven T cell-dependent and TLR7-mediated B cell activation and to assess the additive effects of monocyte/macrophages in this respect.

The glomerular podocytes control filtration barrier permeability in the kidney, and their disturbance underlies the pathogenesis of idiopathic nephrotic syndrome (INS), a kidney disease that predominantly occurs in children. In this study, we found that the interleukin-7 receptor (IL-7R) was induced in the glomeruli of adriamycin (ADR)-induced mouse nephropathy, a rodent model of nephrotic syndrome. In addition, IL-7R was also induced by ADR in mouse podocytes cultured in vitro. Functionally, we discovered that IL-7R activation through the stimulation of recombinant IL-7 induced apoptosis of podocytes, and moreover, IL-7 stimulation inhibited nephrin activation and caused actin cytoskeleton disorganization, indicating that IL-7 stimulation induces podocyte injury. Furthermore, IL-7 stimulation impaired the filtration barrier function of podocyte monolayer. Together, these results identify IL-7 and its receptor IL-7R as potential regulators of podocyte function, which might offer a novel therapeutic target in the treatment of INS.

Mechanisms governing peripheral CD4+ FOXP3+ regulatory T cells (Treg) survival and homeostasis are multiple suggesting tight and complex regulation of regulatory T cells homeostasis. Some specific factors, such as TGF-β, interleukin-2 (IL-2) and B7 costimulatory molecules have been identified as essentials for maintenance of the peripheral Treg compartment. Conversely, Treg dependency upon classical T cell homeostatic factors such as IL-7 is still unclear. In this work, we formally investigated the role of IL-7 in Treg homeostasis in vivo in murine models. We demonstrated that IL-7 availability regulated the size of peripheral Treg cell pool and thus paralleled the impact of IL-7 on conventional T cell pool. Moreover, we showed that IL-7 administration increased Treg cell numbers by inducing thymic-independent Treg peripheral expansion. Importantly the impact of IL-7 on Treg expansion was detected whether conventional T cells were present or absent as IL-7 directly participates to the peripheral expansion of Treg after adoptive transfer into lymphopenic hosts. Our results definitively identify IL-7 as a central factor contributing to Treg peripheral homeostasis, thus reassembling Treg to other T cell subsets in respect of their need for IL-7 for their peripheral maintenance.

Interleukin-7 (IL-7) is a major survival factor for mature T cells. Therefore, the degree of IL-7 availability determines the size of the peripheral T cell pool and regulates T cell homeostasis. Here we provide evidence that IL-7 also regulates the homeostasis of intestinal epithelial cells (IEC), colon function and the composition of the commensal microflora. In the colon of T cell-deficient, lymphopenic mice, IL-7-producing IEC accumulate. IEC hyperplasia can be blocked by IL-7-consuming T cells or the inactivation of the IL-7/IL-7R signaling pathway. However, the blockade of the IL-7/IL-7R signaling pathway renders T cell-deficient mice more sensitive to chemically-induced IEC damage and subsequent colitis. In summary, our data demonstrate that IL-7 promotes IEC hyperplasia under lymphopenic conditions. Under non-lymphopenic conditions, however, T cells consume IL-7 thereby limiting IEC expansion and survival. Hence, the degree of IL-7 availability regulates both, T cell and IEC homeostasis.

The vast majority of Foxp3 regulatory T cells (Treg) exhibits constitutive expression of CD25 (IL-2Rα), which allows the constitution of the high affinity IL-2Rαβγ receptor, ensuring efficient IL-2 binding by Treg. Maintenance of CD25 expression at Treg surface depends on both cell intrinsic factors and environmental stimuli such as IL-2 itself. Whether other factors can participate to maintenance of CD25 expression in vivo is at present unknown. In the present work we demonstrated that IL-7, a gamma-chain cytokine exerting a crucial role in T cell development and homeostasis, is able and necessary to sustain the expression of high levels of CD25 at Treg surface. We demonstrated that, during in vitro cultures performed in the absence of IL-2, IL-7 is able to sustain CD25 expression at Treg surface through a transcriptional mechanism. By studying mice in which IL-7 signaling is either genetically impaired or increased and by employing adoptive transfer murine models, we demonstrated that IL-7 is necessary for sustained expression of CD25 at Treg surface in vivo. To ascertain the biological impact of IL-7 mediated modulation of CD25 expression, we demonstrated that IL-7 modulation of CD25 expression at Treg surface affected their ability to efficiently bind IL-2 and transduce IL-2 signaling. Finally, we demonstrated that IL-7 dependent modulation of CD25 associated with potentiated IL-2 induced expansion of Treg in vivo. Collectively, our results identify IL-7 as a necessary factor contributing to sustained CD25 expression at Treg surface in vivo thereby affecting their ability to efficiently react to IL-2.

Mouse germinal center (GC) B cells have been shown to undergo secondary V(D)J (V, variable; D, diversity; J, joining) recombination (receptor editing) mediated by the reexpressed products of recombination activating gene (RAG)-1 and RAG-2. We show here that interleukin (IL)-7 as well as IL-4 was effective in inducing functional RAG products in mouse IgD+ B cells activated via CD40 in vitro. Blocking of the IL-7 receptor (IL-7R) by injecting an anti- IL-7R monoclonal antibody resulted in a marked suppression of the reexpression of RAG-2 and subsequent V(D)J recombination in the draining lymph node of immunized mice, whereas RAG-2 expression was not impaired in immunized IL-4-deficient mice. Further, these peripheral B cells activated in vitro or in vivo were found to express IL-7R. These findings indicate a novel role for IL-7 and IL-7R in inducing receptor editing in GC B cells.

Cytokines, particularly those of the common gamma chain receptor family, provide extrinsic signals that regulate naive CD4 cell survival. Whether these cytokines are required for the maintenance of memory CD4 cells has not been rigorously assessed. In this paper, we examined the contribution of interleukin (IL) 7, a constitutively produced common gamma chain receptor cytokine, to the survival of resting T cell receptor transgenic memory CD4 cells that were generated in vivo. IL-7 mediated the survival and up-regulation of Bcl-2 by resting memory CD4 cells in vitro in the absence of proliferation. Memory CD4 cells persisted for extended periods upon adoptive transfer into intact or lymphopenic recipients, but not in IL-7- mice or in recipients that were rendered deficient in IL-7 by antibody blocking. Both central (CD62L+) and effector (CD62L-) memory phenotype CD4 cells required IL-7 for survival and, in vivo, memory cells were comparable to naive CD4 cells in this regard. Although the generation of primary effector cells from naive CD4 cells and their dissemination to nonlymphoid tissues were not affected by IL-7 deficiency, memory cells failed to subsequently develop in either the lymphoid or nonlymphoid compartments. The results demonstrate that IL-7 can have previously unrecognized roles in the maintenance of memory in the CD4 cell population and in the survival of CD4 cells with a capacity to become memory cells.

Mice lacking functional IL-7 or IL-7R alpha genes are severely deficient in developing thymocytes, T cells, and B cells. IL-7 and IL-7 receptor functions are believed to result in lymphoid cell proliferation and cell maturation, implying signal transduction pathways directly involved in mitogenesis and elaboration of developmentally specific new gene programs. Here, we show that enforced expression of the bcl-2 gene in T-lymphoid cells (by crossing in the Emu-bcl-2 transgene) in IL-7R alpha-deficient mice results in a significant restoration of thymic positive selection and T cell numbers and function. We propose cell survival signals to be the principal function of IL-7R engagement in thymic and T cell development.

The high-affinity human interleukin-7 (IL-7)R is a heterodimeric complex consisting of the IL-7Ralpha and common interleukin-2 receptor gamma (IL-2Rgamma(c)) chains. Activation of the IL-7R complex is associated with tyrosine and serine residue phosphorylation of a number of intracellular substrates leading to proliferation and induction of various cellular differentiation processes. In this study, we demonstrate, by S1 nuclease protection assay, immunoprecipitation and in vitro kinase assay that functional human (h) IL-7R is expressed in haematopoietic and nonhaematopoietic cell lines. The National Cancer Institute (NCI) tumour panel of 60 cell lines (NCI60) was screened for the expression of IL-7R mRNA by S1 nuclease protection assay, and IL-7R mRNA was detected in 9 of 12 leukemia, 3 of 7 lung, 4 of 6 CNS, 2 of 7 melanoma, 2 of 7 renal, 1 of 6 colon and 1 of 6 breast cancer cell lines. Immunoblot analysis of haematopoietic, lung cancer and brain tumour cell lines demonstrated expression of IL-7R, IL-2Rgamma(c) and p59 fyn, suggesting that the components of an IL-7R signalling network are present in nonhaematopoietic neoplastic cells. Immunoprecipitation of IL-7Ralpha followed by an in vitro kinase assay demonstrated functional receptor phosphorylation events in the lung cancer cells but not in the brain tumour cell lines. The expression of functional IL-7R on epithelial tumour cells may represent a potential target for receptor-directed therapy.

Chimeric antigen receptor (CAR) T cell therapy is routinely used to treat patients with refractory hematologic malignancies. However, a significant proportion of patients experience suboptimal CAR T cell cytotoxicity and persistence that can permit tumor cell escape and disease relapse. Here we show that a prototype pro-lymphoid growth factor is able to enhance CAR T cell efficacy. We demonstrate that a long-acting form of recombinant human interleukin-7 (IL-7) fused with hybrid Fc (rhIL-7-hyFc) promotes proliferation, persistence and cytotoxicity of human CAR T cells in xenogeneic mouse models, and murine CAR T cells in syngeneic mouse models, resulting in long-term tumor-free survival. Thus, rhIL-7-hyFc represents a tunable clinic-ready adjuvant for improving suboptimal CAR T cell activity.

IL7 is a nonredundant cytokine, essential for T cell survival and development in humans. We genotyped nine tagging single nucleotide polymorphisms (SNP), representing all parts of the IL7 gene, in 1,210 Swedish multiple sclerosis (MS) patients and 1,234 healthy controls. None of the SNPs showed a significantly different distribution in MS, and haplotype analysis also failed to reveal differences between patients and controls. We conclude that the IL7 gene is very unlikely to influence the genetic susceptibility to MS in this population.

The cytokine interleukin (IL)-7 exerts essential roles in lymph node (LN) organogenesis and lymphocyte development and homeostasis. Recent studies have identified lymphatic endothelial cells (LECs) as a major source of IL-7 in LNs. Here, we report that LECs not only produce IL-7, but also express the IL-7 receptor chains IL-7Rα and CD132. Stimulation with recombinant IL-7 enhanced LEC in vitro activity and induced lymphangiogenesis in the cornea of wild-type (WT) mice. Whereas in IL-7Rα(-/-) mice, dermal lymphatic vessels (LVs) were abnormally organized and lymphatic drainage was compromised, transgenic overexpression of IL-7 in mice resulted in an expanded dermal LV network with increased drainage function. Moreover, systemic treatment with recombinant IL-7 enhanced lymphatic drainage in the skin of WT mice and of mice devoid of lymphocytes. Experiments in IL-7Rα(-/-) bone marrow chimeras demonstrated that the drainage-enhancing activity of IL-7 was exclusively dependent on IL-7Rα expression in stromal but not in hematopoietic cells. Finally, near-infrared in vivo imaging performed in IL-7Rα(-/-) mice revealed that the pumping activity of collecting vessels was normal but fluid uptake into lymphatic capillaries was defective. Overall, our data point toward an unexpected new role for IL-7 as a potential autocrine mediator of lymphatic drainage.

Interleukin-7 (IL-7) is a central regulator of T cell survival and homeostasis and its expression is indicative for naïve and memory T cells. We cloned chicken IL-7Ralpha (CHIL-7Ralpha) and determined its expression profile in chicken lymphocyte subpopulations. The predicted protein sequence contained 460 amino acids. The extracellular domain exhibited features typical of a type I cytokine receptor; a fibronectin type III domain and the GXWSXWS motif were conserved. ChIL-7Ralpha mRNA is highly expressed in lymphoid organs and in CD4+, CD8alpha+ and CD8beta+ cells. A monoclonal antibody was generated and expression of the protein investigated. ChIL-7Ralpha was expressed on CD4+ and CD8alpha+, but not CD8beta+, T cells, in contrast to the high mRNA expression levels in all of these cells. Upon polyclonal stimulation with ConA, IL-7Ralpha was rapidly down-regulated on T cells, suggesting that in the chicken expression of this receptor might also be correlated to the T cell activation status.

Interleukin 15 (IL15) and IL7 are two cytokines essential for T cell development and homeostasis. In order to improve the antitumor activity by Newcastle disease virus (NDV)-modified tumor vaccine, we generated a recombinant NDV co-expressing IL15 and IL7 (LX/IL(15+7)) through incorporation of a 2A self-processing peptide into IL15 and IL7 using reverse genetics. B16 cells infected with LX/IL(15+7) expressed both IL15 and IL7 stably. The cytotoxicity assay showed that murine melanoma cells modified with LX/IL(15+7) could significantly enhance the antitumor immune response in vitro. Then, the antitumor effects of tumor vaccine modified with recombinant virus were tested in the murine tumor models. We observed strong antitumor responses induced by LX/IL(15+7)-modified tumor cells both in prophylaxis and therapeutic models. Although the tumor-infiltrating CD4+ T cells and CD8+ T cells were both increased, the antitumor activity of the tumor vaccine modified with LX/IL(15+7) was dependent on CD8+ T cells. Taken together, our data strongly indicated that tumor vaccine modified with NDV strain LX/IL(15+7) is a promising agent for cancer immunotherapy.