Induced-Pluripotent-Stem-Cell-Derived Primitive Macrophages Provide a Platform for Modeling Tissue-Resident Macrophage Differentiation and Function.

Tissue macrophages arise during embryogenesis from yolk-sac (YS) progenitors that give rise to primitive YS macrophages. Until recently, it has been impossible to isolate or derive sufficient numbers of YS-derived macrophages for further study, but data now suggest that induced pluripotent stem cells (iPSCs) can be driven to undergo a process reminiscent of YS-hematopoiesis in vitro. We asked whether iPSC-derived primitive macrophages (iMacs) can terminally differentiate into specialized macrophages with the help of growth factors and organ-specific cues. Co-culturing human or murine iMacs with iPSC-derived neurons promoted differentiation into microglia-like cells in vitro. Furthermore, murine iMacs differentiated in vivo into microglia after injection into the brain and into functional alveolar macrophages after engraftment in the lung. Finally, iPSCs from a patient with familial Mediterranean fever differentiated into iMacs with pro-inflammatory characteristics, mimicking the disease phenotype. Altogether, iMacs constitute a source of tissue-resident macrophage precursors that can be used for biological, pathophysiological, and therapeutic studies.

The impact of PIK3CA mutations and PTEN expression on the effect of neoadjuvant therapy for postmenopausal luminal breast cancer patients.

BACKGROUND: There is pressing needs to find the biomarker in the selection of neoadjuvant therapy in postmenopausal luminal breast cancer patients. We examined the hypothesis that PIK3CA mutations and low phosphatase and tensin homolog (PTEN) expression affect the response to neoadjuvant therapy and prognosis in postmenopausal luminal breast cancer patients. METHODS: Postmenopausal patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, up to stage II, who underwent neoadjuvant chemotherapy (NAC; n = 60) or neoadjuvant endocrine therapy (NAE; n = 55) were selected. PIK3CA exon 9 and exon 20 mutations were screened by high resolution melting analysis and confirmed by Sanger sequence. PTEN expression was evaluated by immunohistochemistry. The relationships among PIK3CA mutations, PTEN expression, clinicopathological features, the pathological effect of neoadjuvant therapy, recurrence-free survival (RFS) and overall survival were analyzed. RESULTS: Among 115 patients, PIK3CA mutations and low PTEN expression before treatment were detected in 35 patients (30.4%) and in 28 patients (24.3%), respectively. In the NAC group, tumor with PIK3CA mutations showed significantly poorer response than tumor with PIK3CA wild-type (p = 0.03). On the other hand, in the NAE group, there was no significant difference in pathological therapeutic effect between tumor with PIK3CA mutations and tumor with PIK3CA wild-type (p = 0.54). In the NAC group, the log-rank test showed no difference in RFS between patients with PIK3CA mutations and PIK3CA wild-type (p = 0.43), but patients with low PTEN expression showed significantly worse RFS compared to patients with high PTEN expression (5 year RFS 0.64 vs. 0.87, p = 0.01). In the Cox proportional hazards model for RFS, PTEN expression, progesterone receptor, and pathological therapeutic effect were predictive factors for time to recurrence (All p < 0.05). CONCLUSIONS: PIK3CA mutations are associated with resistance to NAC but do not affect the response to NAE. Low PTEN expression does not affect response to either NAC or NAE but correlates with shorter RFS in patients who received NAC. These biomarkers will be further evaluated for clinical use to treat postmenopausal luminal breast cancer patients.

[Intraoperative Blood Flow Assessment of Gastric Tube Using Indocyanine Green fluorography during Pancreaticoduodenectomy Following Esophagectomy-Case Reports].

Case 1: A 73-year-old male, who had an intraductal papillary mucinous adenocarcinoma or resectable pancreatic cancer at the uncinate process of the pancreas five years after subtotal esophagectomy for esophageal cancer, underwent pylorus preserving pancreaticoduodenectomy(PPPD). Case 2: A 68-year-old male, who also had a resectable pancreatic cancer at the uncinate process of the pancreas 3 years after subtotal esophagectomy for esophageal cancer, underwent PPPD following neoadjuvant chemotherapy. In both cases, right gastroepiploic artery and vein were preserved to maintain the perfusion of the gastric tube during surgery. Indocyanine Green(ICG)fluorography was performed just before duodenal-jejunal anastomosis, which visually showed the well-perfused gastric tube. Both patients had no necrosis of the gastric tube, nor gastrointestinal obstruction after surgery. Intraoperative ICG fluorography was useful to evaluate the blood flow of the remaining gastric tube visually during PPPD for post-esophagectomy patients.

[Conversion Surgery Following Systemic Chemotherapy for Advanced Gallbladder Cancer with Peritoneal Dissemination-A Case Report].

A 73-year-old female was diagnosed with gallbladder cancer, but the future liver remnant volume was deemed insufficient for curative resection. Consequently, transileocolic portal vein embolization was performed. During laparotomy, multiple nodules were palpable on the peritoneal surface of the pelvic floor. Subsequently, staging laparoscopy confirmed the pathological diagnosis of adenocarcinoma in the resected nodules, indicating peritoneal dissemination of gall bladder cancer. Due to this peritoneal dissemination, surgical resection was deemed inappropriate, and the patient was initiated on systemic chemotherapy consisting of gemcitabine and cisplatin. Following 22 courses of chemotherapy, contrast-enhanced computed tomography demonstrated no significant changes in the size of the primary tumor or its location relative to the main vessels, although a small metastatic lesion was identified in the gallbladder bed. At the second staging laparoscopy, any nodules suggesting peritoneal dissemination were observed. Based on these findings, we decided to perform curative resection. The surgical procedure involved right hepatectomy plus segment 4a resection, extrahepatic bile duct resection, and hepaticojejunostomy. Pathological examination revealed ypT3bN0M1(HEP), ypStage ⅣB, with the achievement of R0 resection. The patient survived with no recurrences for 40 months after surgery. These results suggest that aggressive therapeutic strategies, including conversion surgery following systemic chemotherapy, may be beneficial for patients initially deemed unresectable due to gallbladder cancer.

[Retrospective Study of Preoperative Serial Pancreatic Juice Aspiration Cytological Examination(SPACE)for Early Preoperative Detection of Pancreatic Cancer].

Serial pancreatic juice aspiration cytological examination(SPACE)has been reported as a reliable preoperative diagnostic method for early pancreatic cancer, when combined with imaging findings suspecting early pancreatic cancer. Among 259 patients with suspected pancreatic cancer who underwent pancreatic resection at our hospital, SPACE was preoperatively performed in 14 cases(5.4%). Of these 14 cases, final pathological diagnosis was pancreatic cancer in 12 patients (86%), including 5 patients with Stage ⅠA pancreatic cancer(35.7%), all of whom had a mass on preoperative CT or EUS. On the other hand, in the other 2 cases(14.3%), CT/EUS detected no mass but focal pancreatic parenchymal atrophy and main pancreatic duct stenosis which were the imaging findings suspecting very early pancreatic cancer such as cancer in situ. Although preoperative SPACE results of these 2 cases were class Ⅳ, final pathological results of resected specimen were low-grade PanIN in both cases. SPACE was considered useful for preoperative diagnosis of pancreatic cancer in our study, however further study is needed to examine its diagnostic accuracy for early pancreatic cancer which does not appear as a mass in any imaging modality.

Circadian rhythm affects the magnitude of contact hypersensitivity response in mice.

BACKGROUND: The circadian rhythm controls multiple biological processes, including immune responses; however, its impact on cutaneous adaptive immune response remains unclear. METHODS: We used a well-established cutaneous type IV allergy model, contact hypersensitivity (CHS). We induced CHS using dinitrofluorobenzene (DNFB). Mice were sensitized and elicited with DNFB in the daytime or at night. RESULTS: In mice, a nocturnally active animal, we found that ear swelling increased when mice were sensitized at night compared with in the daytime. In addition, cell proliferation and cytokine production in the draining lymph nodes (LNs) were promoted when sensitized at night. We hypothesized that these differences were due to the oscillation of leukocyte distribution in the body through the circadian production of adrenergic hormones. Administration of a ß2-adrenergic receptor (ß2AR) agonist salbutamol in the daytime decreased the number of immune cells in blood and increased the number of immune cells in LNs. In contrast, a ß2AR antagonist ICI18551 administration at night increased the number of immune cells in blood and decreased the number of immune cells in LNs. Accordingly, the severity of CHS response was exacerbated by salbutamol administration in the daytime and attenuated by ICI18551 administration at night. CONCLUSION: Our study demonstrated that the magnitude of adaptive CHS response depends on the circadian rhythm and this knowledge may improve the management of allergic contact dermatitis (ACD) in humans.

[A Case of Central Venous Catheter Fracture after Its Implantation for Liver Metastasis of Rectal and Appendiceal Cancers].

This is the case of a 72-year-old man in whom multiple colorectal cancers including rectal and appendiceal cancers and synchronous S3 liver metastases were observed in 2014, and resection was performed in 2 stages. In 2017, a single recurrence was found in the liver S8, and he underwent a liver S8 sub-segmental resection. Implantation of a CV port for postoperative chemotherapy was planned. At the time of insertion, the catheter was punctured from the exterior portion of the left subclavian vein to avoid the pinch-off syndrome wherein the catheter is crushed between the clavicle and the first rib. Subsequently, FOLFOX therapy was started, but it was discontinued because of allergic symptoms, which appeared during the third course. Two years after the CV port was implanted, a catheter fracture was found on a chest X-ray performed during a regular visit. Since the detached catheter did not fall into the vein, it was possible to remove the port under fluoroscopy. When a catheter is implanted, even under ultrasound guidance, it is considered important to always keep in mind the possibility of a catheter fracture and to detect and respond to it early.

[A Case of Laparoscopic Gastrojejunal Bypass Surgery for Malignant Stenosis after Chemoradiotherapy for Esophageal Cancer].

We report a case of malignant stenosis due to recurrence of lymph node metastasis treated with laparoscopic gastrojejunal bypass. A 83-year-old man who underwent chemoradiotherapy for esophageal cancer(cT3N2M0). About 3 and half years after chemoradiotherapy, he was referred to hospital for vomiting. As a result of the examination, we diagnosed malignant stenosis of descending part of duodenum due to retroperitoneum lymph node recurrence of esophageal cancer. We performed laparoscopic gastrojejunal bypass operation because we suggested self-expandable metallic stent make easy to migrate into anal side of the duodenum. The postoperative course was good. He was enrolled in oncology department on the 21 days after the operation. Gastroduodenal stenosis is common pathology by malignant tumor. Gastrojejunostomy and placement of self-expandable metallic stent is commonly performed for malignant gastroduodenal obstruction. Endoscopic metallic stent placement is minimally invasive treatment for malignant stenosis of the intestine, however sometime the stent placement will make easy to migrate by extra compression. Gastrojejunostomy mat be more safety than endoscopic stent placement for the malignant gastroduodenal obstruction.

Metastatic peripancreatic lymph nodes resection during primary debulking surgery for primary peritoneal serous carcinoma.

OBJECTIVE: Metastatic lymph node resection around the porta hepatis is sometimes required to achieve complete cytoreduction for ovarian, fallopian tube, and primary peritoneal cancer. Hence, this study aimed to present the surgical approach of peripancreatic lymph node removal around the porta hepatis as part of primary debulking surgery. METHODS: A 75-year old woman with stage IIIC primary peritoneal serous carcinoma underwent primary debulking surgery by means of the following procedures: bilateral salpingo-oophorectomy, total hysterectomy, omentectomy, total pelvic peritonectomy, rectosigmoid colectomy with anastomosis, right hemicolectomy, right diaphragm resection, partial jejunal resection, and pelvic and para-aortic lymphadenectomy. Furthermore, she underwent enlarged peripancreatic lymph nodes resection located in the hepatoduodenal ligament and on the posterior pancreatic head. An anatomic variant of the common hepatic artery was identified to be arising from the superior mesenteric artery and not from the celiac artery. The common hepatic artery ran behind the portal vein. We resected the lymph nodes without causing injury of the hepatic artery, portal vein, and common bile duct and achieved complete cytoreduction. RESULTS: The histological examination revealed high-grade serous carcinoma in three of nine resected peripancreatic lymph nodes. In contrast, only one lymph node metastasized in the interaortocaval region among the 63 resected regional lymph nodes (paraaortic and pelvic lymph nodes). CONCLUSION: Metastatic peripancreatic lymph nodes resection around the porta hepatis is feasible and sometimes necessary for cytoreductive surgery for advanced ovarian, fallopian tube, and primary peritoneal cancer.

Outcomes of surgical resection for gastric cancer liver metastases: a retrospective analysis.

BACKGROUND: The indications for the surgical treatment of gastric cancer liver metastases (GCLMs) remain controversial. In addition, the outcome of surgery for the treatment of liver metastases of alpha-fetoprotein-producing gastric cancer (AFP-GC) has not yet been reported. We assessed the clinicopathologic features, including AFP-GC, and the surgical results of these patients. METHODS: This retrospective study analyzed 20 patients who underwent hepatectomy for GCLM at Odawara Municipal Hospital between April 2006 and January 2016. RESULTS: The actuarial 1-, 3-, and 5-year overall survival (OS) rates after primary hepatectomy were 80.0%, 55.5%, and 31.7%, respectively, with a median OS of 42 months. Four patients survived for more than 5 years after their final hepatectomy procedures. A multivariate analysis showed multiple metastases in the liver, the elevated level of carbohydrate antigen 19-9 (CA19-9), and an age of less than 70 years to be independently associated with a poor prognosis in terms of OS. No significant differences were noted between the AFP-GC and AFP-negative GC groups. CONCLUSION: Surgical treatment is therefore considered to be a feasible option for GCLM. The findings of the present study showed the number of metastatic liver tumors, the level of CA19-9, and the patient age to be prognostic indicators for the surgical treatment of GCLM.

Cutaneous p38 mitogen-activated protein kinase activation triggers psoriatic dermatitis.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease characterized by IL-17-mediated immune responses. p38 is known to be highly activated in the psoriatic epidermis; however, whether p38 is involved in the development of psoriasis is unclear. OBJECTIVE: We sought to demonstrate that activation of p38 mitogen-activated protein kinase is sufficient to induce psoriatic inflammation in mice and that cutaneous p38 activities are the topical therapeutic targets for psoriasis. METHODS: A p38 activator, anisomycin, was applied daily to murine skin. Transcriptomic analyses were performed to evaluate the similarities of the skin responses to those in human psoriasis and the existing animal model. BIRB796, a small-molecule inhibitor targeting p38 activities, was applied to the murine psoriatic models topically or to human psoriatic skin specimens ex vivo. RESULTS: Topical treatment with anisomycin induced key signatures in psoriasis, such as epidermal thickening, neutrophil infiltration, and gene expression of Il1a, Il1b, Il6, Il24, Cxcl1, Il23a, and Il17a, in treated murine skin. These responses were fully abrogated by topical treatment with BIRB796, and were reduced in IL-17A-deficient mice. Transcriptomic analyses demonstrated the similarities of anisomycin-induced dermatitis to human psoriasis and imiquimod-induced murine psoriatic dermatitis. Furthermore, BIRB796 targeting of p38 activities reduced expression of psoriasis-related genes in both human keratinocytes stimulated with recombinant IL-17A in vitro and psoriatic skin specimens ex vivo. CONCLUSION: Therefore our findings suggest that cutaneous p38 activation can be a key event in patients with psoriasis and a potential topical therapeutic target of a small molecule.

[A Case of Synchronous Colorectal Cancer Successfully Treated by Laparoscopic Surgery with Two Segmental Anastomoses].

A 63-year-old man was admitted for the evaluation of Hb 4.8 g/dL anemia. He underwent colon fiberscopy and was subsequently diagnosed with synchronous cancers of the ascending colon and rectum. He underwent laparoscopic ileocecal resection and low anterior resection with 2 segmental anastomoses. The histopathological diagnosis of A/C and rectal cancer was Stage Ⅱ and Stage Ⅲa, respectively. His treatment was completed after 6months of adjuvant chemotherapy with oral TS-1, which was followed by a subsequent 2 year follow-up study, without disease recurrence. Operations of synchronous cancers with 2 segmental anastomoses usually require longer surgical time and are associated with more postoperative complications compared with a single segmental anastomosis. We report a case of synchronous colorectal cancer successfully treated by laparoscopic surgery with 2 segmental anastomoses.

[A Case of Long-Term Survival in a Patient with Recurrence of Peritoneal Dissemination after Resection of Pancreatic Tail Cancer].

A 60-year-old man underwent distal pancreatectomy with splenectomy and combined resection partially of the stomach, jejunum, and left renal vein. We administered S-1 adjuvant chemotherapy for 1 year. After its completion, the patient showed no evidence of recurrence. However, his carbohydrate antigen(CA)19-9 level was elevated for 1 year and 8 months postoperatively. We administered gemcitabine chemotherapy. He was admitted for bowel obstruction 3 years and 10 months postoperatively. Conservative treatment with an ileus tube did not improve the bowel obstruction. Therefore, we performed the surgery. Intraoperative findings revealed peritoneal nodules invading the small intestine. We performed a small bowel bypass. Pathological examination revealed the peritoneal nodule of pancreatic cancer. Although we administered FOLFIRINOX chemotherapy postoperatively, his CA19-9 level remained elevated for 4 years and 8 months after the first surgery. Therefore, chemotherapy was changed to gemcitabine and nab-paclitaxel. Six years and 11 months after the first surgery and 5 years and 3 months after the diagnosis of peritoneal dissemination, he survives with recurrence. Herein, there were 2 contributors to long-term survival; the patient not only showed positive responses to each chemotherapy regimen but could also continue chemotherapy without developing significant adverse effects.

[A Case of Pancreatic Mucinous Cystic Carcinoma with Bilateral Lung Metastases].

A 48-year-old female visited former doctor with abdominal pain and bloating. She was suspected of having pancreatic tumor and referred to our hospital. Abdominal dynamic CT showed multilocular cystic tumor in the pancreatic tail, and chest CT showed multiple lung nodules. From these findings, the patient was diagnosed mucinous cystic carcinoma(MCC)with lung metastases. We performed distal pancreatectomy for the first and lung resection after pancreatectomy. After all, the pathological diagnosis was MCC and metastatic lung cancer from the MCC. The adjuvant chemotherapy was not performed. Eleven months after pancreatectomy and 6 months after lung resection, the patient is still alive without recurrence.

APOBEC3 regulates keratinocyte differentiation and expression of Notch3.

Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family consists of deaminases. Some isozymes of APOBEC3 are induced upon human papillomavirus infection or development of psoriasis skin lesions. However, the involvement of APOBEC3 in keratinocyte differentiation has not been addressed. We herein sought to evaluate the roles of APOBECs in mouse primary keratinocyte differentiation. We found that expression levels of APOBEC1 and APOBEC3 were increased during calcium-induced keratinocyte differentiation. Unexpectedly, however, the expression levels of keratinocyte differentiation markers keratin 1/10, involucrin, loricrin and filaggrin were higher in keratinocytes treated with APOBEC3 siRNAs than in those treated with control RNAs. In addition, the treatment of keratinocytes with APOBEC3 siRNAs increased the gene expression levels of Notch3, a master regulator of keratinocyte differentiation. Moreover, calcium-induced increase in Notch3 expression and keratinocyte differentiation were impaired by transfection with an APOBEC3 expression plasmid. Furthermore, co-treatment with Notch3 siRNAs reduced the APOBEC3 siRNA-mediated upregulation of Notch3 expression and in part attenuated the increased expression levels of keratinocyte differentiation markers. These results suggest that APOBEC3 is induced upon keratinocyte differentiation and negatively regulates the keratinocyte differentiation in part by its inhibitory role for Notch3 expression.

[A Case of Laparoscopic Gastrojejunostomy for Duodenal Obstruction Caused by Unresectable Locally Advanced Pancreatic Cancer].

The patient was an 85-year-old man who received chemotherapy with gemcitabine for 2 years 9 months under the diagnosis of unresectable locally advanced pancreatic body and tail cancer. He visited our hospital because of anorexia, upper abdominal fullness, and vomiting. A CT scan showed severe stenosis in the third portion of the duodenum, which was associated with the direct invasion of the advanced pancreatic cancer. Upper gastrointestinal fiberscopy revealed a severe duodenal obstruction; however, pancreatic cancer exposure within the duodenal mucosa was not observed. As the stenosis of the duodenum was relatively smooth because of the cancer invasion into only the submucosa, deviation of the metallic stent was possible, so we performed laparoscopic gastrojejunostomy. We started the surgery with 5-port settings. A slit was made in the gastric body by using ENDO-GIA®, and bypass surgery with a Roux-en-Y anastomosis was performed. The postoperative course was good, and oral intake resumed on the third postoperative day. Thereafter, he could leave the hospital with good progress and received systemic chemotherapy using gemcitabine. In the present case, an extramural gastrointestinal stenosis without cancer that was not exposed in the gastrointestinal mucosa was poorly fixed with gastrointestinal metallic stents and use of a deviating metallic stent was reported, so we chose laparoscopic gastrojejunostomy. In addition, after undergoing laparoscopic surgery, which is a minimally invasive treatment, he recovered quickly and shifted early to systemic chemotherapy. Herein, the usefulness of laparoscopic gastrojejunostomy for extramural stenosis is reported with a review of related literature.

[A Case of Locally Recurrent Tumor Resected by Left Hemicolectomy with Left Nephrectomy Six Years after Curative Operation for Sigmoid Colon Cancer].

A 65-year-old woman underwent high anterior resection for sigmoid colon cancer in 2011. The histopathological diagnosis was type 2, 25×27 mm, tub2, SE, N2, ly2, v1, and Stage Ⅲb. Her treatment was completed after 6months of adjuvant chemotherapy with UFT plus UZEL followed by a 5-year follow-up study, without recurrence. However, 6years after the initial operation, a routine chest and abdominal CT scan showed a 24mm local recurrence involving the left urinary tract and bilateral lung lesions. Eight courses of systemic chemotherapy using FOLFOX plus panitumumab regimen was administered immediately. CT scan after chemotherapy showed that all masses were downsized and no new lesions were identified. We resected the recurrent tumor after considering it feasible by left hemicolectomy with left nephrectomy. Histopathological examination of the recurrent tumor revealed adenocarcinoma, consistent with that of the previous primary sigmoid colon cancer. She is currently undergoing systemic chemotherapy using the FOLFOX regimen. There has been no change in the lung lesions and no new lesions have developed. This is a very rare case of recurrence more than 5 years after curative resection of Stage Ⅲ colon cancer. This paper presents the case considering that keeping the patient under surveillance for more than 5 years enabled the disclosure of recurrence without subjective symptoms.

Immune-complex level of cofilin-1 in sera is associated with cancer progression and poor prognosis in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. To improve its outcome, reliable biomarkers are urgently needed. In this study, we aimed to elucidate the key molecules involved in PDAC progression using proteomics approaches. First, we undertook 2-D electrophoresis to identify the proteins overexpressed in PDAC tissues. Following the analysis of agarose gel spots, cofilin-1 was identified and verified as a candidate protein commonly upregulated in PDAC tissues. In immunohistochemistry, cofilin-1 was strongly expressed in the cytoplasm of PDAC cells. Samples were divided into two groups based on the level of cofilin-1 expression. The high expression group showed significantly higher incidence of hematogenous dissemination in relapsed patients than the low expression group (P = 0.0083). In in vitro experiments, knockdown of cofilin-1 significantly decreased chemotaxis in PDAC cell lines. After we confirmed that cofilin-1 was secreted from PDAC cells, we established a detection system for the immune-complex of cofilin-1 in sera. Using this system, we measured the IC levels of cofilin-1 in sera and observed that the IC levels of cofilin-1 in PDAC patients were higher than those in healthy volunteers and patients with pancreatitis (PDAC vs. healthy volunteers, P < 0.0001; PDAC vs. patients with pancreatitis, P < 0.026). Notably, the IC levels of cofilin-1 showed a stepwise increase during PDAC progression (P = 0.0034), and high IC levels of cofilin-1 indicated poor prognosis of patients after surgery (P = 0.039). These results suggest that the IC of cofilin-1 in sera is a potentially attractive serum biomarker for the prognosis of PDAC.

Reduced interleukin-2 responsiveness impairs the ability of Treg cells to compete for IL-2 in nonobese diabetic mice.

Enhancement of regulatory T cell (Treg cell) frequency and function is the goal of many therapeutic strategies aimed at treating type 1 diabetes (T1D). The interleukin-2 (IL-2) pathway, which has been strongly implicated in T1D susceptibility in both humans and mice, is a master regulator of Treg cell homeostasis and function. We investigated how IL-2 pathway defects impact Treg cells in T1D-susceptible nonobese diabetic (NOD) mice in comparison with protected C57BL/6 and NOD congenic mice. NOD Treg cells were reduced in frequency specifically in the lymph nodes and expressed lower levels of CD25 and CD39/CD73 immunosuppressive molecules. In the spleen and blood, Treg cell frequency was preserved through expansion of CD25(low), effector phenotype Treg cells. Reduced CD25 expression led to decreased IL-2 signaling in NOD Treg cells. In vivo, treatment with IL-2-anti-IL-2 antibody complexes led to effective upregulation of suppressive molecules on NOD Treg cells in the spleen and blood, but had reduced efficacy on lymph node Treg cells. In contrast, NOD CD8(+) and CD4(+) effector T cells were not impaired in their response to IL-2 therapy. We conclude that NOD Treg cells have an impaired responsiveness to IL-2 that reduces their ability to compete for a limited supply of IL-2.