The Broad Immunomodulatory Effects of IL-7 and Its Application In Vaccines.

Interleukin-7 (IL-7) is produced by stromal cells, keratinocytes, and epithelial cells in host tissues or tumors and exerts a wide range of immune effects mediated by the IL-7 receptor (IL-7R). IL-7 is primarily involved in regulating the development of B cells, T cells, natural killer cells, and dendritic cells via the JAK-STAT, PI3K-Akt, and MAPK pathways. This cytokine participates in the early generation of lymphocyte subsets and maintain the survival of all lymphocyte subsets; in particular, IL-7 is essential for orchestrating the rearrangement of immunoglobulin genes and T-cell receptor genes in precursor B and T cells, respectively. In addition, IL-7 can aid the activation of immune cells in anti-virus and anti-tumor immunity and plays important roles in the restoration of immune function. These biological functions of IL-7 make it an important molecular adjuvant to improve vaccine efficacy as it can promote and extend systemic immune responses against pathogens by prolonging lymphocyte survival, enhancing effector cell activity, and increasing antigen-specific memory cell production. This review focuses on the biological function and mechanism of IL-7 and summarizes its contribution towards improved vaccine efficacy. We hope to provide a thorough overview of this cytokine and provide strategies for the development of the future vaccines.

Intrathymic Deletion of IL-7 Reveals a Contribution of the Bone Marrow to Thymic Rebound Induced by Androgen Blockade.

Despite the well-documented effect of castration in thymic regeneration, the singular contribution of the bone marrow (BM) versus the thymus to this process remains unclear. The chief role of IL-7 in pre- and intrathymic stages of T lymphopoiesis led us to investigate the impact of disrupting this cytokine during thymic rebound induced by androgen blockade. We found that castration promoted thymopoiesis in young and aged wild-type mice. In contrast, only young germline IL-7-deficient (Il7-/- ) mice consistently augmented thymopoiesis after castration. The increase in T cell production was accompanied by the expansion of the sparse medullary thymic epithelial cell and the peripheral T cell compartment in young Il7-/- mice. In contrast to young Il7-/- and wild-type mice, the poor thymic response of aged Il7-/- mice after castration was associated with a defect in the expansion of BM hematopoietic progenitors. These findings suggest that BM-derived T cell precursors contribute to thymic rebound driven by androgen blockade. To assess the role of IL-7 within the thymus, we generated mice with conditional deletion of IL-7 (Il7 conditional knockout [cKO]) in thymic epithelial cells. As expected, Il7cKO mice presented a profound defect in T cell development while maintaining an intact BM hematopoietic compartment across life. Unlike Il7-/- mice, castration promoted the expansion of BM precursors and enhanced thymic activity in Il7cKO mice independently of age. Our findings suggest that the mobilization of BM precursors acts as a prime catalyst of castration-driven thymopoiesis.

Permissive roles of cytokines interleukin-7 and Flt3 ligand in mouse B-cell lineage commitment.

Hematopoietic cells are continuously generated throughout life from hematopoietic stem cells, thus making hematopoiesis a favorable system to study developmental cell lineage commitment. The main factors incorporating environmental signals to developing hematopoietic cells are cytokines, which regulate commitment of hematopoietic progenitors to the different blood lineages by acting either in an instructive or a permissive manner. Fms-like tyrosine kinase-3 (Flt3) ligand (FL) and Interleukin-7 (IL-7) are cytokines pivotal for B-cell development, as manifested by the severely compromised B-cell development in their absence. However, their precise role in regulating B-cell commitment has been the subject of debate. In the present study we assessed the rescue of B-cell commitment in mice lacking IL-7 but simultaneously overexpressing FL. Results obtained demonstrate that FL overexpression in IL-7-deficient mice rescues B-cell commitment, resulting in significant Ebf1 and Pax5 expression in Ly6D+CD135+CD127+CD19- precursors and subsequent generation of normal numbers of CD19+ B-cell progenitors, therefore indicating that IL-7 can be dispensable for commitment to the B-cell lineage. Further analysis of Ly6D+CD135+CD127+CD19- progenitors in IL-7- or FL-deficient mice overexpressing Bcl2, as well as in IL-7 transgenic mice suggests that both FL and IL-7 regulate B-cell commitment in a permissive manner: FL by inducing proliferation of Ly6D+CD135+CD127+CD19- progenitors and IL-7 by providing survival signals to these progenitors.

Interleukin-7 is required for CD4(+) T cell activation and autoimmune neuroinflammation.

IL-7 is known to be vital for T cell homeostasis but has previously been presumed to be dispensable for TCR-induced activation. Here, we show that IL-7 is critical for the initial activation of CD4(+) T cells in that it provides some of the necessary early signaling components, such as activated STAT5 and Akt. Accordingly, short-term in vivo IL-7Rα blockade inhibited the activation and expansion of autoantigen-specific CD4(+) T cells and, when used to treat experimental autoimmune encephalomyelitis (EAE), prevented and ameliorated disease. Our studies demonstrate that IL-7 signaling is a prerequisite for optimal CD4(+) T cell activation and that IL-7R antagonism may be effective in treating CD4(+) T cell-mediated neuroinflammation and other autoimmune inflammatory conditions.

Stromal-Derived Factor-1α and Interleukin-7 Treatment Improves Homeostatic Proliferation of Naïve CD4(+) T Cells after Allogeneic Stem Cell Transplantation.

Graft-versus-host disease (GVHD) impairs immune reconstitution after allogeneic stem cell transplantation (allo-SCT) and effective therapies aimed at restoring T cell counts in GVHD patients have yet to be developed. During GVHD, CD4(+) T cell reconstitution is particularly affected and current models hold that GVHD insult to the peripheral lymphoid niche is responsible for this effect. Here, we show that naïve CD4(+) T cell homeostatic proliferation (HP) is lost during GVHD because of low systemic IL-7 and impaired dendritic cell (DC) regeneration. We assessed factors involved in DC differentiation and found that although fms-like tyrosine kinase 3 ligand (Flt3-L) levels were normal, stromal-derived factor-1α (SDF-1α) was diminished in the blood of GVHD mice. Unlike Flt3-L treatment, the administration of SDF-1α specifically increased CD8α(+) DC numbers and did not worsen GVHD. Importantly, CD4(+) T cell HP was enhanced only when IL-7 and SDF-1α or Flt3L were coadministered, confirming the crucial role of DCs and IL-7 in restoring CD4(+) T cell regeneration during GVHD. Altogether, our results indicate that CD8α(+) DCs are part of the peripheral niche that controls CD4(+) T cell HP and that their depletion, combined with low systemic IL-7, explains how GVHD constrains naïve CD4(+) T cell reconstitution after allo-SCT.

IL-7 coordinates proliferation, differentiation and Tcra recombination during thymocyte ß-selection.

Signaling via the pre-T cell antigen receptor (pre-TCR) and the receptor Notch1 induces transient self-renewal (ß-selection) of TCRß(+) CD4(-)CD8(-) double-negative stage 3 (DN3) and DN4 progenitor cells that differentiate into CD4(+)CD8(+) double-positive (DP) thymocytes, which then rearrange the locus encoding the TCR α-chain (Tcra). Interleukin 7 (IL-7) promotes the survival of TCRß(-) DN thymocytes by inducing expression of the pro-survival molecule Bcl-2, but the functions of IL-7 during ß-selection have remained unclear. Here we found that IL-7 signaled TCRß(+) DN3 and DN4 thymocytes to upregulate genes encoding molecules involved in cell growth and repressed the gene encoding the transcriptional repressor Bcl-6. Accordingly, IL-7-deficient DN4 cells lacked trophic receptors and did not proliferate but rearranged Tcra prematurely and differentiated rapidly. Deletion of Bcl6 partially restored the self-renewal of DN4 cells in the absence of IL-7, but overexpression of BCL2 did not. Thus, IL-7 critically acts cooperatively with signaling via the pre-TCR and Notch1 to coordinate proliferation, differentiation and Tcra recombination during ß-selection.

Deficit of interleukin 7 in septic patients.

We recently demonstrated an overall decrease of all αß and specially γδ T cell subsets in patients with sepsis compared with healthy subjects. IL-7 is a crucial factor for development of γδ T cells and survival in sepsis but its association with sepsis severity, evolution of organ failure and death still has not been investigated. Sera from 78 patients who met criteria for sepsis were analyzed vs control group. Septic patients showed the lowest levels of IL-7. Patients with severe sepsis reached levels of IL-7 higher than those observed in the groups of uncomplicated sepsis and septic shock. The frequency of γδ T cells at admission was lower in septic patients vs control group. At the time of admission, the frequency of γδ T cells in septic patients who subsequently died was lower than the observed in the group of patients that instead survived.

The expanding role of IL-7 and thymic stromal lymphopoietin as therapeutic target for rheumatoid arthritis.

INTRODUCTION: The discovery of IL-7 and thymic stromal lymphopoietin (TSLP) has been a major step in the understanding of arthritis. IL-7 amplifies the inflammation induced by other cytokines, primarily TNF. In animal models of arthritis, inhibition of IL-7 limits inflammation and joint erosion. TSLP is an IL-7-like cytokine that triggers dendritic cell-mediated Th2-type inflammatory responses and is considered as a master switch for allergic inflammation. TSLP is a downstream molecule of TNF-α and as such may be involved in the pathophysiology of inflammatory arthritis. AREAS COVERED: This review summarizes current knowledge of the role of IL-7 and TSLP derived from both animal models and studies in patients with rheumatoid arthritis (RA). The emergence of IL-7 blockade as a future therapy in RA is highlighted, along with the potential goals and limitations of this therapeutic approach. The write-up also highlights the functional capacities of TSLP in arthritis. EXPERT OPINION: Evidences suggest important roles for IL-7 and TSLP in the pathogenesis of RA and can be viewed as potential therapeutic targets. Regulation of these at genetic level is a promising investigational area. Given the difficulty in reconstituting T cells in patients with RA, therapeutic approaches that minimize the elimination of T cells are likely to be more desirable.

The transcription factor E4BP4 is not required for extramedullary pathways of NK cell development.

NK cells contribute to antitumor and antiviral immunosurveillance. Their development in the bone marrow (BM) requires the transcription factor E4BP4/NFIL3, but requirements in other organs are less well defined. In this study, we show that CD3(-)NK1.1(+)NKp46(+)CD122(+) NK cells of immature phenotype and expressing low eomesodermin levels are found in thymus, spleen, and liver of E4BP4-deficient mice, whereas numbers of mature, eomesodermin(high) conventional NK cells are drastically reduced. E4BP4-deficient CD44(+)CD25(-) double-negative 1 thymocytes efficiently develop in vitro into NK cells with kinetics, phenotype, and functionality similar to wild-type controls, whereas no NK cells develop from E4BP4-deficient BM precursors. In E4BP4/Rag-1 double-deficient (DKO) mice, NK cells resembling those in Rag-1-deficient controls are found in similar numbers in the thymus and liver. However, NK precursors are reduced in DKO BM, and no NK cells develop from DKO BM progenitors in vitro. DKO thymocyte precursors readily develop into NK cells, but DKO BM transfers into nude recipients and NK cells in E4BP4/Rag-1/IL-7 triple-KO mice indicated thymus-independent NK cell development. In the presence of T cells or E4BP4-sufficient NK cells, DKO NK cells have a selective disadvantage, and thymic and hepatic DKO NK cells show reduced survival when adoptively transferred into lymphopenic hosts. This correlates with higher apoptosis rates and lower responsiveness to IL-15 in vitro. In conclusion, we demonstrate E4BP4-independent development of NK cells of immature phenotype, reduced fitness, short t1/2, and potential extramedullary origin. Our data identify E4BP4-independent NK cell developmental pathways and a role for E4BP4 in NK cell homeostasis.

Role of hepatocyte-derived IL-7 in maintenance of intrahepatic NKT cells and T cells and development of B cells in fetal liver.

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-7(f/f) Alb-Cre mice compared with IL-7(f/f) control mice. In contrast, NK cells, dendritic cells, and B cells were unchanged in the IL-7(f/f) Alb-Cre liver. The number of Vα14(+) invariant NKT cells was significantly reduced in liver, but not in thymus and spleen, of IL-7(f/f) Alb-Cre mice. Furthermore, B cell development was impaired in perinatal liver of IL-7(f/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.

Regulation of in vitro human T cell development through interleukin-7 deprivation and anti-CD3 stimulation.

BACKGROUND: The role of IL-7 and pre-TCR signaling during T cell development has been well characterized in murine but not in human system. We and others have reported that human BM hematopoietic progenitor cells (HPCs) display poor proliferation, inefficient double negative (DN) to double positive (DP) transition and no functional maturation in the in vitro OP9-Delta-like 1 (DL1) culture system. RESULTS: In this study, we investigated the importance of optimal IL-7 and pre-TCR signaling during adult human T cell development. Using a modified OP9-DL1 culture ectopically expressing IL-7 and Fms-like tyrosine kinase 3 ligand (Flt3L), we demonstrated enhanced T cell precursor expansion. IL-7 removal at various time points during T cell development promoted a slight increase of DP cells; however, these cells did not differentiate further and underwent cell death. As pre-TCR signaling rescues DN cells from programmed cell death, we treated the culture with anti-CD3 antibody. Upon pre-TCR stimulation, the IL-7 deprived T precursors differentiated into CD3+TCRαß+DP cells and further matured into functional CD4 T cells, albeit displayed a skewed TCR Vß repertoire. CONCLUSIONS: Our study establishes for the first time a critical control for differentiation and maturation of adult human T cells from HPCs by concomitant regulation of IL-7 and pre-TCR signaling.

Osteoblast-specific overexpression of human interleukin-7 rescues the bone mass phenotype of interleukin-7-deficient female mice.

Interleukin-7 is a critical cytokine for lymphoid development and a direct inhibitor of in vitro osteoclastogenesis in murine bone marrow cultures. To explore the role of IL-7 in bone, we generated transgenic mouse lines bearing the 2.3-kb rat collagen 1α1 promoter driving the expression of human IL-7 specifically in osteoblasts. In addition, we crossed these mice with IL-7-deficient mice to determine if the alterations in lymphopoiesis, bone mass, and osteoclast formation observed in the IL-7 knockout (KO) mice could be rescued by osteoblast-specific overexpression of IL-7. Here, we show that mice overexpressing human IL-7 in the osteoblast lineage showed increased trabecular bone volume in vivo by µCT and decreased osteoclast formation in vitro. Furthermore, targeted overexpression of IL-7 in osteoblasts rescued the osteopenic bone phenotype and B-cell development of IL-7 KO mice but did not have an effect on T lymphopoiesis, which occurs in the periphery. The bone phenotypes in IL-7 KO mice and targeted IL-7-overexpressing mouse models were observed only in females. These results likely reflect both direct inhibitory effects of IL-7 on osteoclastogenesis in vivo and sex-specific differences in responses to IL-7.

IL-7 uniquely maintains FoxP3(+) adaptive Treg cells that reverse diabetes in NOD mice via integrin-ß7-dependent localization.

Type 1 diabetes (T1D) develops as a consequence of a progressive autoimmune response that destroys insulin-producing ß-cells in pancreatic islets. Because of their role(s) in controlling immune responses, considerable effort has been directed toward resolving whether regulatory T cells (Tregs) offer a clinical treatment to restore tolerance in T1D. We previously reported that in vitro-induced adaptive Treg cells (aTregs) can reverse T1D and persist as protective memory cells in the NOD mouse model. In the current study, we investigated mechanisms that regulate aTregs. We found that these FoxP3(+) aTregs expressed high levels of the IL-7 receptor, IL-7Rα, without the high affinity receptor for IL-2, CD25, which is found on natural Treg cells (nTregs). IL-7Rα expression was mirrored by the dependency of aTregs on IL-7 for persistence. IL-10 and TGF-ß, effector cytokines of aTregs, were not essential for their maintenance at the level of systemic antibody blocking. Nevertheless, IL-10 modulated cytokine production by aTregs and TGF-ß was critical for protection. aTregs were found to infiltrate islets and the expression of integrin-ß7 was required for their localization in the pancreas. Furthermore, blocking aTreg entry into the pancreas prevented their control of diabetogenic effector T cells, implying the need for local control of the autoimmune response. The distinct homeostatic regulation of aTregs independently of a response to IL-2, which is defective in T1D patients, suggests that these cells represent a translatable candidate to control the autoimmune response.

Post-operative infection and sepsis in humans is associated with deficient gene expression of γc cytokines and their apoptosis mediators.

INTRODUCTION: Lymphocyte homeostasis is dependent on the γc cytokines. We hypothesised that sepsis in humans is associated with differential gene expression of the γc cytokines and their associated apoptosis mediators. METHODS: The study population consisted of a total of 60 patients with severe sepsis, 15 with gram negative bacteraemia, 10 healthy controls and 60 patients undergoing elective lung resection surgery. Pneumonia was diagnosed by CDC NNIC criteria. Gene expression in peripheral blood leukocytes (PBLs) of interleukin (IL)-2, 7, 15 and interferon (IFN)-γ, Bax, Bim, Bcl-2 was determined by qRT-PCR and IL-2 and IL-7 serum protein levels by ELISA. Gene expression of IL-2, 7 and IFN-γ was measured in peripheral blood leukocytes (PBL), cultured in the presence of lipopolysaccharide (LPS) and CD3 binding antibody (CD3ab) RESULTS: IL-2 gene expression was lower in the bacteraemia group compared with controls, and lower still in the sepsis group (P < 0.0001). IL-7 gene expression was similar in controls and bacteraemia, but lower in sepsis (P < 0.0001). IL-15 gene expression was similar in the three groups. Bcl-2 gene expression was less (P < 0.0001) and Bim gene expression was greater (P = 0.0003) in severe sepsis compared to bacteraemic and healthy controls. Bax gene expression was similar in the three groups.In lung resection surgery patients, post-operative pneumonia was associated with a perioperative decrease in IL-2 mRNA (P < 0.0001) and IL-7 mRNA (P = 0.003). IL-2 protein levels were reduced in sepsis and bacteraemia compared to controls (P = 0.02) but similar in pneumonia and non-pneumonia groups. IL-7 protein levels were similar in all groups.In cultured PBLs, IFN-γ gene expression was decreased in response to LPS and increased in response to CD3ab with sepsis: IL-7 gene expression increased in response to LPS in controls and to CD3ab with sepsis; Bcl-2 gene expression decreased in response to combined CD3ab and IL-2 with sepsis. CONCLUSIONS: Patients with infection and sepsis have deficient IL-2 and IL-7 gene expression in PBLs. Aberrant cytokine gene expression may precede the onset of infection.

Effect of age on homeostasis of lymphocytes in an interleukin-7-deficient mouse model.

Interleukin (IL)-7 is thought to be a non-redundant cytokine for lymphopoiesis as there is a reduction of T and B cells in peripheral blood (PB) and a loss of TCRγδ+ cells in PB and bone marrow (BM) in IL-7⁻/⁻ mice. To investigate whether the absence of IL-7 influences the organ-dependent distribution of the lymphocytes, we analyzed single cell suspensions of several organs (BM, lung, liver, small intestine, and spleen) at different ages (three and 12 months) of IL-7+/+ and IL-7⁻/⁻ mice using flow cytometry; immunohistochemical staining was performed on frozen sections of various organs. We observed lymphocytopenia in almost all organs of IL-7⁻/⁻ mice, but normal counts in the liver and the lung of three-month-old IL-7⁻/⁻ mice. CD4+ and CD8+ cell numbers were decreased in the spleen and the BM. With aging, we found a greater increase in CD4+ and CD8+ cells in the BM of IL-7⁻/⁻ than in IL-7+/+ mice, particularly of memory cells. The spleen of IL-7⁻/⁻ mice was characterized by lymphocytopenia. We challenge the view that IL-7 is a non-redundant cytokine for lymphocyte development. Some of the changes observed, e.g. partial absence of TCRγδ+ T cells in the PB, BM and small intestine and complete loss in liver, lung and spleen, may be due to the altered organ distribution instead of a defect in γδ+ T cell lymphopoiesis. In this model, aging leads to a significantly altered composition of lymphocyte subsets, and the lack of IL-7 seems to accelerate this process.

Kit ligand and Il7 differentially regulate Peyer's patch and lymph node development.

Hematopoietic lymphoid tissue inducer (LTi) cells initiate lymph node (LN) and Peyer's patch (PP) development during fetal life by inducing the differentiation of mesenchymal organizer cells. The growth factor signals underlying LTi cell development and LN and PP organogenesis remain poorly understood. LTi cells express the Il7r and the receptor tyrosine kinase Kit, whereas organizer cells express their cognate ligands. To determine the relative significance of Il7 and Kit signaling in LTi cell homeostasis and PP and LN development, we have analyzed mice deficient for Kit (Kit(W/Wv)), Il7 (Il7(-/-)), or both (Il7(-/-) Kit(W/Wv)). Unlike Kit(W/Wv) and Il7(-/-) single mutants, Il7(-/-) Kit(W/Wv) mice were almost devoid of LTi cells in their mesenteric LN anlage. This LTi deficiency was associated with a block in mesenchymal LN organizer cell generation and the absence of almost all LNs. In contrast, intestinal LTi cell numbers, PP organizer cell generation, and PP development were strongly affected by impaired Kit signaling, but were independent of Il7. Hence, Kit and Il7 act synergistically in LN organogenesis, whereas Kit signaling, but not Il7, critically regulates PP organogenesis and LTi cell numbers in the intestine. Consistent with these differential growth factor requirements for PP and LN development, PP organizer cells expressed higher Kitl and lower Il7 levels than did LN organizer cells. Collectively, these results demonstrate that Kit and Il7 differentially control PP and LN organogenesis through the local growth factor-driven regulation of LTi cell numbers.

Absence of both IL-7 and IL-15 severely impairs the development of CD8 T cell response against Toxoplasma gondii.

CD8(+) T cells play an essential role in the protection against both acute as well as chronic Toxoplasma gondii infection. Although the role of IL-15 has been reported to be important for the development of long-term CD8(+) T cell immunity against the pathogen, the simultaneous roles played by both IL-15 and related gamma-chain family cytokine IL-7 in the generation of this response during acute phase of infection has not been described. We demonstrate that while lack of IL-7 or IL-15 alone has minimal impact on splenic CD8(+) T cell maturation or effector function development during acute Toxoplasmosis, absence of both IL-7 and IL-15 only in the context of infection severely down-regulates the development of a potent CD8(+) T cell response. This impairment is characterized by reduction in CD44 expression, IFN-gamma production, proliferation and cytotoxicity. However, attenuated maturation and decreased effector functions in these mice are essentially downstream consequences of reduced number of antigen-specific CD8(+) T cells. Interestingly, the absence of both cytokines did not impair initial CD8(+) T cell generation but affected their survival and differentiation into memory phenotype IL-7Ralpha(hi) cells. Significantly lack of both cytokines severely affected expression of Bcl-2, an anti-apoptotic protein, but minimally affected proliferation. The overarching role played by these cytokines in eliciting a potent CD8(+) T cell immunity against T. gondii infection is further evidenced by poor survival and high parasite burden in anti IL-7 treated IL-15(-/-) mice. These studies demonstrate that the two cytokines, IL-7 and IL-15, are exclusively important for the development of protective CD8(+) T cell immune response against T. gondii. To the best of our knowledge this synergism between IL-7 and IL-15 in generating an optimal CD8(+) T cell immunity against intracellular parasite or any other infectious disease model has not been previously reported.

IL-7-dependent B lymphocytes are essential for the anti-polysaccharide response and protective immunity to Streptococcus pneumoniae.

Young children are impaired in their response to T cell-independent (TI) Ags, such as pneumococcal polysaccharide (PPS). B lymphopoeisis early in life is IL-7 independent, whereas in adults it is IL-7 dependent. Therefore, we hypothesized that IL-7-driven B lymphopoiesis plays a critical role in promoting Ab responses to TI Ags. Young but not adult mice are impaired in responses to PPS vaccination and to 4-hydroxy-3-nitrophenyl-acetyl-Ficoll, a widely studied model TI Ag, and B1b cells generate Ab responses to these Ags. In this paper, we show that, despite having B1b, B1a, and MZ B cells-all of which are involved in TI responses-young wild-type or adult mice deficient either in IL-7 or in IL-7Ralpha are severely impaired in anti-PPS responses and do not survive Streptococcus pneumoniae challenge, indicating IL-7-dependent B cells are required for TI immunity. Consistent with this, PPS immunization induced a robust TI response in young IL-7 transgenic mice that was comparable to adult wild-type responses. Moreover, immunized young or adult IL-7 transgenic mice were completely resistant to S. pneumoniae challenge. Our data indicate that activating the IL-7 signaling pathway could restore impaired TI responses in the young.

Cutting edge: IL-7 regulates the peripheral pool of adult ROR gamma+ lymphoid tissue inducer cells.

During fetal life, CD4(+)CD3(-) lymphoid tissue inducer (LTi) cells are required for lymph node and Peyer's patch development in mice. In adult animals, CD4(+)CD3(-) cells are found in low numbers in lymphoid organs. Whether adult CD4(+)CD3(-) cells are LTi cells and are generated and maintained through cytokine signals has not been directly addressed. In this study we show that adult CD4(+)CD3(-) cells adoptively transferred into neonatal CXCR5(-/-) mice induced the formation of intestinal lymphoid tissues, demonstrating for the first time their bona fide LTi function. Increasing IL-7 availability in wild-type mice either by IL-7 transgene expression or treatment with IL-7/anti-IL-7 complexes increased adult LTi cell numbers through de novo generation from bone marrow cells and increased the survival and proliferation of LTi cells. Our observations demonstrate that adult CD4(+)lineage(-) cells are LTi cells and that the availability of IL-7 determines the size of the adult LTi cell pool.