A RORE-dependent Intronic Enhancer in the IL-7 Receptor-α Locus Controls Glucose Metabolism via Vγ4+ γδT17 Cells.

The IL-7R regulates the homeostasis, activation, and distribution of T cells in peripheral tissues. Although several transcriptional enhancers that regulate IL-7Rα expression in αß T cells have been identified, enhancers active in γδ T cells remain unknown. In this article, we discovered an evolutionarily conserved noncoding sequence (CNS) in intron 2 of the IL-7Rα-chain (IL-7Rα) locus and named this region CNS9. CNS9 contained a conserved retinoic acid receptor-related orphan receptor (ROR)-responsive element (RORE) and exerted RORγt-dependent enhancer activity in vitro. Mice harboring point mutations in the RORE in CNS9 (CNS9-RORmut) showed reduced IL-7Rα expression in IL-17-producing Vγ4+ γδ T cells. In addition, the cell number and IL-17A production of Vγ4+ γδ T cells were reduced in the adipose tissue of CNS9-RORmut mice. Consistent with the reduction in IL-17A, CNS9-RORmut mice exhibited decreased IL-33 expression in the adipose tissue, resulting in fewer regulatory T cells and glucose intolerance. The CNS9-ROR motif was partially responsible for IL-7Rα expression in RORγt+ regulatory T cells, whereas IL-7Rα expression was unaffected in RORγt-expressing Vγ2+ γδ T cells, Th17 cells, type 3 innate lymphoid cells, and invariant NKT cells. Our results indicate that CNS9 is a RORΕ-dependent, Vγ4+ γδ T cell-specific IL-7Rα enhancer that plays a critical role in adipose tissue homeostasis via regulatory T cells, suggesting that the evolutionarily conserved RORΕ in IL-7Rα intron 2 may influence the incidence of type 2 diabetes.

A Chimeric IL-7Rα/IL-2Rß Receptor Promotes the Differentiation of T Cell Progenitors into B Cells and Type 2 Innate Lymphoid Cells.

IL-7 and IL-2 are evolutionarily related cytokines that play critical roles in the development and expansion of immune cells. Although both IL-7R and IL-2R activate similar signaling molecules, whether their signals have specific or overlapping functions during lymphocyte differentiation remains unclear. To address this question, we generated IL-7R α-chain (IL-7Rα)/IL-2R ß-chain (IL-24ß) (72R) knock-in mice expressing a chimeric receptor consisting of the extracellular domain of IL-7Rα and the intracellular domain of IL-2Rß under the control of the endogenous IL-7Rα promoter. Notably, this 72R receptor induced higher levels of STAT5 and Akt phosphorylation in T cells. In the periphery of 72R mice, the number of T cells, B cells, and type 2 innate lymphoid cells (ILC2s) was increased, whereas early T cell progenitors and double-negative 2 thymocytes were reduced in the thymus. In addition, cell proliferation and Notch signaling were impaired in the early thymocytes of 72R mice, leading to their differentiation into thymic B cells. Interestingly, ILC2s were increased in the thymus of 72R mice. Early T cell progenitors from 72R mice, but not from wild-type mice, differentiated into NK cells and ILC2-like cells when cocultured with a thymic stromal cell line. Thus, this study indicates that the chimeric 72R receptor transduces more robust signals than the authentic IL-7Rα, thereby inducing the alternative differentiation of T cell progenitors into other cell lineages. This suggests that cytokine receptors may provide instructive signals for cell fate decisions.

Clinical Practice Guidelines for the Management of Congenital Cytomegalovirus Infection in Japan 2023: Executive Summary.

Congenital cytomegalovirus (cCMV) infection is the most common congenital infection in developed countries. Although a standard therapy has not yet been established, evidence for the management of cCMV infection has been accumulating. The first edition of the "Clinical Practice Guidelines for the Management of Congenital Cytomegalovirus Infection" was published in Japan in 2023. This summary outlines the clinical questions (CQs) in the guidelines, with reference to the Japanese Medical Information Distribution Service Manual. Overall, 20 CQs with statements regarding prenatal risk assessment, prevention and management at diagnosis (CQs 1-1-1-3), diagnosis (CQs 2-1-2-6), treatment (CQs 3-1-3-7) and follow-up requirements (CQs 4-1-4-4) have been discussed. For each statement, the levels of recommendation, evidence and consensus rates were determined. These guidelines will assist in the management of patients with cCMV infection.

Robotic Versus Laparoscopic Abdominoperineal Resection for Locally Advanced Rectal Cancer Following Preoperative Chemoradiotherapy.

BACKGROUND/AIM: The usefulness of robotic surgery compared to laparoscopic surgery for rectal cancer has been reported; however, few reports exist on robotic abdominoperineal resection (APR). The aim of this study was to compare the outcomes of robotic and laparoscopic surgery to determine their usefulness in patients with locally advanced rectal cancer who had undergone preoperative chemoradiotherapy (CRT). PATIENTS AND METHODS: This retrospective study included 43 patients with locally advanced rectal cancer who underwent preoperative CRT and robotic (22 patients) or laparoscopic APR (21 patients) between December 2012 and September 2022. We examined the short- and long-term outcomes in the robotic and laparoscopic groups. RESULTS: The median follow-up durations were 36 and 48 months for the robotic and laparoscopic groups, respectively. No significant differences in operative time, intraoperative blood loss, or overall complication rates were observed. However, the incidence of organ/space surgical site infection (SSI) was significantly lower in the robotic surgery group than in the laparoscopic group (9.1% vs. 38.1%, p=0.034) and the 3-year overall survival rate was significantly higher in the robotic surgery group than in the laparoscopic group (95% vs. 67%, p=0.029). CONCLUSION: Robotic APR was associated with a significantly lower rate of organ/space SSIs than the laparoscopic approach, indicating the usefulness of the robotic approach.

Nutritional Status Indicators Predict Tolerability to Adjuvant Chemotherapy in Patients with Stage II/III Rectal Cancer Undergoing Neoadjuvant Chemoradiotherapy.

INTRODUCTION: Adjuvant chemotherapy (AC) after radical surgery following preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC) is now the standard of care. The identification of risk factors for the discontinuation of AC is important for further improvements in survival. We herein examined the prognostic impact of chemotherapy compliance and its relationship with the prognostic nutritional index (PNI) before surgery. METHODS: A total of 335 stage II-III LARC patients who underwent preoperative CRT between 2003 and 2022 at the University of Tokyo Hospital were retrospectively reviewed. We excluded patients with recurrence during AC and those who had not received AC. The relationship between AC and long-term outcomes and that between PNI values and the duration of AC were examined. RESULTS: Thirty-one patients discontinued AC and 62 continued AC. Recurrence-free survival (RFS) was significantly shorter in patients who discontinued AC (p = 0.0056). The discontinuation of AC was identified as an independent risk factor for RFS (hazard ratio [HR]: 2.24, p = 0.0233). Twenty-one patients were classified as having low PNI (less than 40), which correlated with an older age, low body mass index, and incomplete AC. Low PNI was an independent risk factor for a shorter duration of AC (HR: 2.53, p = 0.0123). CONCLUSION: The discontinuation of AC was related to poor RFS in patients with LARC undergoing preoperative CRT. Furthermore, a low PNI value was identified as a risk factor for a shorter duration of AC.

Evaluation of anorectal function using real-time tissue elastography before and after preoperative chemoradiotherapy.

PURPOSE: This study aimed to clarify the relationship between changes in elasticity and anorectal function before and after chemoradiotherapy. METHODS: This is a single-center prospective cohort study (Department of Surgical Oncology, The University of Tokyo). We established a technique to quantify internal anal sphincter hardness as elasticity using transanal ultrasonography with real-time tissue elastography. Twenty-seven patients with post-chemoradiotherapy rectal cancer during 2019-2022 were included. Real-time tissue elastography with transanal ultrasonography was performed before and after chemoradiotherapy to measure internal anal sphincter hardness as "elasticity" (hardest (0) to softest (255); decreased elasticity indicated sclerotic changes). The relationship between the increase or decrease in elasticity pre- and post-chemoradiotherapy and the maximum resting pressure, maximum squeeze pressure, and Wexner score were the outcome measures. RESULTS: A decrease in elasticity was observed in 16/27 (59.3%) patients after chemoradiotherapy. Patients with and without elasticity decrease after chemoradiotherapy comprised the internal anal sphincter sclerosis and non-sclerosis groups, respectively. The maximum resting pressure post-chemoradiotherapy was significantly high in the internal anal sphincter sclerosis group (63.0 mmHg vs. 47.0 mmHg), and a majority had a worsening Wexner score (60.0% vs. 18.2%) compared with that of the non-sclerosis group. Decreasing elasticity (internal anal sphincter sclerosis) correlated with a higher maximum resting pressure (r = 0.36); no correlation was observed between the degree of elasticity change and maximum squeeze pressure. CONCLUSION: Internal anal sphincter sclerosis due to chemoradiotherapy may correlate to anorectal dysfunction.

Differences in the Difficulty of Accessing Various 3-Dimensional Locations Under Mirror-Image Conditions During Laparoscopic Surgery.

BACKGROUND: Laparoscopic colon surgery frequently requires performing maneuvers under mirror-images conditions; the complexity differs depending on the surgical site location in the abdominal cavity. However, no previous reports have examined this. METHODS: Eleven surgeons participated in this study. Operations were performed on 25 points placed at the bottom and sides of a laparoscopic training box under mirror-image conditions. The mean time-point required to operate at each point and variation between surgeons were evaluated. RESULTS: When the right hand was used, time-points to touch the right side-superficial ends were 0.50 to 0.58 and 0.27 to 0.45 for the other sites. With the left hand, time-points to touch the left side-superficial ends were 0.58 to 0.63 and 0.28 to 0.51 for the other sites, indicating that the most difficult manipulation was at the proximal site of the surgical port. The variation in the difficulty according to the spots increased with a decrease in the surgeon's experience (right hand, r =-0.248; left hand, r =-0.491). CONCLUSIONS: In performing laparoscopic surgery under mirror-image conditions, the technical difficulty varies by location, and operating in locations close to the forceps port is the most difficult.

Minimally invasive versus open multivisceral resection for rectal cancer clinically invading adjacent organs: a propensity score-matched analysis.

BACKGROUND: Minimally invasive surgery (MIS), such as laparoscopic and robotic surgery for rectal cancer, is performed worldwide. However, limited information is available on the advantages of MIS over open surgery for multivisceral resection for cases clinically invading adjacent organs. PATIENTS AND METHODS: This was a retrospective propensity score-matching study of consecutive clinical T4b rectal cancer patients who underwent curative intent surgery between 2006 and 2021 at the University of Tokyo Hospital. RESULTS: Sixty-nine patients who underwent multivisceral resection were analyzed. Thirty-three patients underwent MIS (the MIS group), while 36 underwent open surgery (the open group). Twenty-three patients were matched to each group. Conversion was required in 2 patients who underwent MIS (8.7%). R0 resection was achieved in 87.0% and 91.3% of patients in the MIS and open groups, respectively. The MIS group had significantly less blood loss (170 vs. 1130 mL; p < 0.0001), fewer Clavien-Dindo grade ≥ 2 postoperative complications (30.4% vs. 65.2%; p = 0.0170), and a shorter postoperative hospital stay (20 vs. 26 days; p = 0.0269) than the open group. The 3-year cancer-specific survival rate, relapse-free survival rate, and cumulative incidence of local recurrence were 75.7, 35.9, and 13.9%, respectively, in the MIS group and 84.5, 45.4, and 27.1%, respectively, in the open group, which were not significantly different (p = 0.8462, 0.4344, and 0.2976, respectively). CONCLUSION: MIS had several short-term advantages over open surgery, such as lower complication rates, faster recovery, and a shorter hospital stay, in rectal cancer patients who underwent multivisceral resection.

Control of the Development, Distribution, and Function of Innate-Like Lymphocytes and Innate Lymphoid Cells by the Tissue Microenvironment.

Recently, considerable attention has been directed toward innate-like T cells (ITCs) and innate lymphoid cells (ILCs) owing to their indispensable contributions to immune responses, tissue homeostasis, and inflammation. Innate-like T cells include NKT cells, MAIT cells, and γδ T cells, whereas ILCs include NK cells, type 1 ILCs (ILC1s), type 2 ILCs (ILC2s), and type 3 ILCs (ILC3s). Many of these ITCs and ILCs are distributed to specific tissues and remain tissue-resident, while others, such as NK cells and some γδ T cells, circulate through the bloodstream. Nevertheless, recent research has shed light on novel subsets of innate immune cells that exhibit characteristics intermediate between tissue-resident and circulating states under normal and pathological conditions. The local microenvironment frequently influences the development, distribution, and function of these innate immune cells. This review aims to consolidate the current knowledge on the functional heterogeneity of ITCs and ILCs, shaped by local environmental cues, with particular emphasis on IL-15, which governs the activities of the innate immune cells involved in type 1 immune responses.

Insights into the heterogeneity of iNKT cells: tissue-resident and circulating subsets shaped by local microenvironmental cues.

Invariant natural killer T (iNKT) cells are a distinct subpopulation of innate-like T lymphocytes. They are characterized by semi-invariant T cell receptors (TCRs) that recognize both self and foreign lipid antigens presented by CD1d, a non-polymorphic MHC class I-like molecule. iNKT cells play a critical role in stimulating innate and adaptive immune responses, providing an effective defense against infections and cancers, while also contributing to chronic inflammation. The functions of iNKT cells are specific to their location, ranging from lymphoid to non-lymphoid tissues, such as the thymus, lung, liver, intestine, and adipose tissue. This review aims to provide insights into the heterogeneity of development and function in iNKT cells. First, we will review the expression of master transcription factors that define subsets of iNKT cells and their production of effector molecules such as cytokines and granzymes. In this article, we describe the gene expression profiles contributing to the kinetics, distribution, and cytotoxicity of iNKT cells across different tissue types. We also review the impact of cytokine production in distinct immune microenvironments on iNKT cell heterogeneity, highlighting a recently identified circulating iNKT cell subset. Additionally, we explore the potential of exploiting iNKT cell heterogeneity to create potent immunotherapies for human cancers in the future.

Local excision versus radical surgery for anal squamous cell carcinoma: a multicenter study in Japan.

BACKGROUND: The standard treatment for anal squamous cell carcinoma is chemoradiation therapy (CRT), but there is a possibility of over-treatment for early-stage disease. cTisN0 and cT1N0 disease is currently indicated for local excision, but it is unclear whether the indication of local excision can be expanded to cT2N0 disease. METHODS: 126 patients with cTis-T2N0 anal cancer treated at 47 centers in Japan between 1991 and 2015 were included. Patients were first classified into the CRT group and surgical therapy group according to the initial therapy, and the latter was further divided into local excision (LE) and radical surgery (RS) groups. We compared prognoses among the groups, and analyzed risk factors for recurrence after local excision. RESULTS: The CRT group (n = 87) and surgical therapy group (n = 39) showed no difference in relapse-free survival (p = 0.29) and overall survival (p = 0.94). Relapse-free survival curves in the LE (n = 23) and RS groups (n = 16) overlapped for the initial 3 years, but the curve for the LE group went lower beyond (p = 0.33). By contrast, there was no difference in overall survival between the two groups (p = 0.98). In the LE group, the majority of recurrences distributed in locoregional areas, which could be managed by salvage treatments. Muscular invasion was associated with recurrence after local excision (hazard ratio: 22.91, p = 0.011). CONCLUSION: LE may be applied to selected patients with anal cancer of cTis-T2N0 stage. Given the high risk of recurrence in cases with muscular invasion, it may be important to consider close surveillance and additional treatment in such patients.

Range of protein induced by vitamin K absence or antagonist-II levels in neonates at birth.

Protein induced by vitamin K absence or antagonist-II (PIVKA-II) is avitamin K (VK) deficiency indicator in neonates. However, PIVKA-II detection frequency in neonatal blood at birth and the correlation between PIVKA-II and gestational age are unclear. We retrospectively analyzed infants admitted to our institution between June 1, 2018, and March 31, 2022, whose clinical and PIVKA-II data were available, and classified them into preterm and term infant groups. Overall incidence of PIVKA-II-positive cases (≥ 50 mAU/mL) was 42.8%, including 0.6% apparent VK deficiency (≥ 5000 mAU/mL), 3.1% experimental VK deficiency (1000-4999 mAU/mL), and 10.7% latent VK deficiency (200-999 mAU/mL) cases. Incidence of PIVKA-II-positive cases was significantly higher in the term group than in the preterm group (49.4% vs. 29.7%, p < 0.001). Gestational age correlated with PIVKA-II levels (r2 = 0.117, p < 0.0001). Median serum PIVKA-II levels and incidence of PIVKA-II-positive cases (≥ 50 mAU/mL, 16.4%) were lower at 5 days after birth than at birth, possibly reflecting the postnatal VK prophylaxis impact. Only one infant was diagnosed with VK deficiency bleeding (PIVKA-II levels, at birth: 10,567 mAU/mL; at day 5: 2418 mAU/mL). Thus, serum PIVKA-II levels after birth weakly correlated with gestational age. VK deficiency was more common in term infants than in preterm infants.

Essential anatomy for lateral lymph node dissection.

In Western countries, the gold-standard therapeutic strategy for rectal cancer is preoperative chemoradiotherapy (CRT) following total mesorectal excision (TME), without lateral lymph node dissection (LLND). However, preoperative CRT has recently been reported to be insufficient to control lateral lymph node recurrence in cases of enlarged lateral lymph nodes before CRT, and LLND is considered necessary in such cases. We performed a literature review on aspects of pelvic anatomy associated with rectal surgery and LLND, and then combined this information with our experience and knowledge of pelvic anatomy. In this review, drawing upon research using a 3-dimensional anatomical model and actual operative views, we aimed to clarify the essential anatomy for LLND. The LLND procedure was developed in Asian countries and can now be safely performed in terms of functional preservation. Nonetheless, the longer operative time, hemorrhage, and higher complication rates with TME accompanied by LLND than with TME alone indicate that LLND is still a challenging procedure. Laparoscopic or robotic LLND has been shown to be useful and is widely performed; however, without a sufficient understanding of anatomical landmarks, misrecognition of vessels and nerves often occurs. To perform safe and accurate LLND, understanding the landmarks of LLND is essential.

Unexplained increases in serum carcinoembryonic antigen levels in colorectal cancer patients during the postoperative follow-up period: an analysis of its incidence and longitudinal pattern.

BACKGROUND: Carcinoembryonic antigen (CEA) monitoring facilitates the detection of recurrence in patients with colorectal cancer (CRC) after resection. False-positive CEA has been reported in CRC patients with certain comorbidities or smokers. However, limited information is currently available on the frequency of and changes in falsely elevated CEA levels in patients without these conditions. MATERIALS AND METHODS: We retrospectively examined CRC patients who underwent surgical resection at our hospital between 2001 and 2017, had no recurrence for at least five years, and were free of known factors that may increase CEA. Postoperative CEA levels were retrieved until 2 years before the last contact. For comparison, we similarly selected patients who developed recurrence after resection of CRC during the same period, and CEA levels at initial presentation, at nadir, and at the time of recurrence were reviewed. The patterns of elevated CEA (>5 ng/ml) were classified as transient, repeated, or persistent based on longitudinal changes. The relationships between CEA and carbohydrate antigen 19-9, transaminases, creatinine, and C-reactive protein were examined. RESULTS: CEA elevation occurred in 90 (20%) out of 446 eligible patients without recurrence at least once during the mean postoperative period of 50.5 months, whereas CEA was >5 ng/ml in 117 (53%) of 221 patients when they developed recurrence. Twenty-seven patients without recurrence showed a transient elevation in CEA, 45 repeated elevations, and 18 a persistent elevation; the frequency of a high preoperative CEA level increased in this order. The majority (98%) of false elevations ranged between 5 and 15 ng/ml. CEA was not associated with other laboratory data. CONCLUSIONS: Unexplained CEA elevations were observed in 20% of recurrence-free CRC patients after surgery, and were classified into three patterns based on longitudinal changes. A more detailed understanding of patient-specific fluctuations in CEA will prevent unnecessary imaging studies and reduce medical costs.

Limited information is currently available on the frequency of and changes in falsely elevated carcinoembryonic antigen (CEA) levels after surgery for colorectal cancer. Unexplained postoperative CEA elevations were detected in 20% of colorectal cancer patients. The patterns of these elevations were classified into transient, repeated, and persistent.

Hematopoietic cell-derived IL-15 supports NK cell development in scattered and clustered localization within the bone marrow.

Natural killer (NK) cells are innate immune cells critical for protective immune responses against infection and cancer. Although NK cells differentiate in the bone marrow (BM) in an interleukin-15 (IL-15)-dependent manner, the cellular source of IL-15 remains elusive. Using NK cell reporter mice, we show that NK cells are localized in the BM in scattered and clustered manners. NK cell clusters overlap with monocyte and dendritic cell accumulations, whereas scattered NK cells require CXCR4 signaling. Using cell-specific IL-15-deficient mice, we show that hematopoietic cells, but not stromal cells, support NK cell development in the BM through IL-15. In particular, IL-15 produced by monocytes and dendritic cells appears to contribute to NK cell development. These results demonstrate that hematopoietic cells are the IL-15 niche for NK cell development in the BM and that BM NK cells are present in scattered and clustered compartments by different mechanisms, suggesting their distinct functions in the immune response.

CD45 alleviates airway inflammation and lung fibrosis by limiting expansion and activation of ILC2s.

Group 2 innate lymphoid cells (ILC2s) are critical for the immune response against parasite infection and tissue homeostasis and involved in the pathogenesis of allergy and inflammatory diseases. Although multiple molecules positively regulating ILC2 development and activation have been extensively investigated, the factors limiting their population size and response remain poorly studied. Here, we found that CD45, a membrane-bound tyrosine phosphatase essential for T cell development, negatively regulated ILC2s in a cell-intrinsic manner. ILC2s in CD45-deficient mice exhibited enhanced proliferation and maturation in the bone marrow and hyperactivated phenotypes in the lung with high glycolytic capacity. Furthermore, CD45 signaling suppressed the type 2 inflammatory response by lung ILC2s and alleviated airway inflammation and pulmonary fibrosis. Finally, the interaction with galectin-9 influenced CD45 signaling in ILC2s. These results demonstrate that CD45 is a cell-intrinsic negative regulator of ILC2s and prevents lung inflammation and fibrosis via ILC2s.

Benefits of a laparoscopic approach for second colorectal resection after colectomy or proctectomy -a retrospective study.

BACKGROUND: A laparoscopic approach generally provides several benefits in patients who undergo colon or rectal surgery without jeopardizing oncological outcomes. However, there is a paucity of studies on comparative outcomes of laparoscopic versus open approaches for second primary colorectal lesions after colectomy or proctectomy. METHODS: From patients with colorectal disease who underwent surgery between 2008 and 2022 at our hospital, we collected 69 consecutive patients who had previous colorectal surgery for this retrospective study. Based on the second surgery approach (laparoscopic or open), patients were classified into the Lap (n = 37) or Op group (n = 32). Patients' baseline data and perioperative and postoperative outcomes were compared between the two groups. RESULTS: Four patients (11%) of the Lap group needed conversion to laparotomy. The intraoperative blood loss was lower in the Lap group than the Op group (median: 45 ml vs. 205 ml, p = 0.001). The time to first bowel movement was shorter in the Lap group than the Op group (median: 2.8 days vs. 3.6 days, p = 0.007). The operative time, frequencies of postoperative morbidities, and overall survival did not differ between the two groups. CONCLUSION: Laparoscopic surgery appeared feasible and beneficial for selected patients undergoing second colorectal resection after colectomy or proctectomy regarding blood loss and bowel function recovery without affecting other outcomes.

Lung group 2 innate lymphoid cells differentially depend on local IL-7 for their distribution, activation, and maintenance in innate and adaptive immunity-mediated airway inflammation.

Interleukin-7 (IL-7) is a cytokine critical for the development and maintenance of group 2 innate lymphoid cells (ILC2s). ILC2s are resident in peripheral tissues such as the intestine and lung. However, whether IL-7 produced in the lung plays a role in the maintenance and function of lung ILC2s during airway inflammation remains unknown. IL-7 was expressed in bronchoalveolar epithelial cells and lymphatic endothelial cells (LECs). To investigate the role of local IL-7 in lung ILC2s, we generated two types of IL-7 conditional knockout (IL-7cKO) mice: Sftpc-Cre (SPC-Cre) IL-7cKO mice specific for bronchial epithelial cells and type 2 alveolar epithelial cells and Lyve1-Cre IL-7cKO mice specific for LECs. In steady state, ILC2s were located near airway epithelia, although lung ILC2s were unchanged in the two lines of IL-7cKO mice. In papain-induced airway inflammation dependent on innate immunity, lung ILC2s localized near bronchia via CCR4 expression, and eosinophil infiltration and type 2 cytokine production were reduced in SPC-Cre IL-7cKO mice. In contrast, in house dust mite (HDM)-induced airway inflammation dependent on adaptive immunity, lung ILC2s localized near lymphatic vessels via their CCR2 expression 2 weeks after the last challenge. Furthermore, lung ILC2s were decreased in Lyve1-Cre IL-7cKO mice in the HDM-induced inflammation because of decreased cell survival and proliferation. Finally, administration of anti-IL-7 antibody attenuated papain-induced inflammation by suppressing the activation of ILC2s. Thus, this study demonstrates that IL-7 produced by bronchoalveolar epithelial cells and LECs differentially controls the activation and maintenance of lung ILC2s, where they are localized in airway inflammation.

Liver type 1 innate lymphoid cells lacking IL-7 receptor are a native killer cell subset fostered by parenchymal niches.

Group 1 innate lymphoid cells (G1-ILCs), including circulating natural killer (NK) cells and tissue-resident type 1 ILCs (ILC1s), are innate immune sentinels critical for responses against infection and cancer. In contrast to relatively uniform NK cells through the body, diverse ILC1 subsets have been characterized across and within tissues in mice, but their developmental and functional heterogeneity remain unsolved. Here, using multimodal in vivo approaches including fate-mapping and targeting of the interleukin 15 (IL-15)-producing microenvironment, we demonstrate that liver parenchymal niches support the development of a cytotoxic ILC1 subset lacking IL-7 receptor (7 R- ILC1s). During ontogeny, fetal liver (FL) G1-ILCs arise perivascularly and then differentiate into 7 R- ILC1s within sinusoids. Hepatocyte-derived IL-15 supports parenchymal development of FL G1-ILCs to maintain adult pool of 7 R- ILC1s. IL-7R+ (7R+) ILC1s in the liver, candidate precursors for 7 R- ILC1s, are not essential for 7 R- ILC1 development in physiological conditions. Functionally, 7 R- ILC1s exhibit killing activity at steady state through granzyme B expression, which is underpinned by constitutive mTOR activity, unlike NK cells with exogenous stimulation-dependent cytotoxicity. Our study reveals the unique ontogeny and functions of liver-specific ILC1s, providing a detailed interpretation of ILC1 heterogeneity.