Interleukin (IL)-21 is the most recently recognized of the cytokines that share the common cytokine receptor γ chain (γc), which is mutated in humans with X-linked severe combined immunodeficiency. We now report that IL-21 synergistically acts with IL-15 to potently promote the proliferation of both memory (CD44high) and naive (CD44low) phenotype CD8+ T cells and augment interferon-γ production in vitro. IL-21 also cooperated, albeit more weakly, with IL-7, but not with IL-2. Correspondingly, the expansion and cytotoxicity of CD8+ T cells were impaired in IL-21R−/− mice. Moreover, in vivo administration of IL-21 in combination with IL-15 boosted antigen-specific CD8+ T cell numbers and resulted in a cooperative effect on tumor regression, with apparent cures of large, established B16 melanomas. Thus, our studies reveal that IL-21 potently regulates CD8+ T cell expansion and effector function, primarily in a synergistic context with IL-15.

Objective To evaluate the effect of coronavirus disease 2019 (COVID‐19) on maternal, perinatal and neonatal outcome by performing a systematic review of available published literature on pregnancies affected by COVID‐19. Methods We performed a systematic review to evaluate the effect of COVID‐19 on pregnancy, perinatal and neonatal outcome. We conducted a comprehensive literature search using PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure Database and Wan Fang Data up to and including 20 April 2020 (studies were identified through PubMed alert after that date). For the search strategy, combinations of the following keywords and medical subject heading (MeSH) terms were used: ‘SARS‐CoV‐2’, ‘COVID‐19’, ‘coronavirus disease 2019’, ‘pregnancy’, ‘gestation’, ‘maternal’, ‘mother’, ‘vertical transmission’, ‘maternal–fetal transmission’, ‘intrauterine transmission’, ‘neonate’, ‘infant’ and ‘delivery’. Eligibility criteria included laboratory‐confirmed and/or clinically diagnosed COVID‐19, patient being pregnant on admission and availability of clinical characteristics, including at least one maternal, perinatal or neonatal outcome. Exclusion criteria were non‐peer‐reviewed or unpublished reports, unspecified date and location of the study, suspicion of duplicate reporting and unreported maternal or perinatal outcomes. No language restrictions were applied. Results We identified a high number of relevant case reports and case series, but only 24 studies, including a total of 324 pregnant women with COVID‐19, met the eligibility criteria and were included in the systematic review. These comprised nine case series (eight consecutive) and 15 case reports. A total of 20 pregnant patients with laboratory‐confirmed COVID‐19 were included in the case reports. In the combined data from the eight consecutive case series, including 211 (71.5%) cases of laboratory‐confirmed and 84 (28.5%) of clinically diagnosed COVID‐19, the maternal age ranged from 20 to 44 years and the gestational age on admission ranged from 5 to 41 weeks. The most common symptoms at presentation were fever, cough, dyspnea/shortness of breath, fatigue and myalgia. The rate of severe pneumonia reported amongst the case series ranged from 0% to 14%, with the majority of the cases requiring admission to the intensive care unit. Almost all cases from the case series had positive computed tomography chest findings. All six and 22 cases that had nucleic‐acid testing in vaginal mucus and breast milk samples, respectively, were negative for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Only four cases of spontaneous miscarriage or termination were reported. In the consecutive case series, 219/295 women had delivered at the time of reporting and 78% of them had Cesarean section. The gestational age at delivery ranged from 28 to 41 weeks. Apgar scores at both 1 and 5 min ranged from 7 to 10. Only eight neonates had birth weight < 2500 g and nearly one‐third of neonates were transferred to the neonatal intensive care...

The aim of this study was to investigate the clinical characteristics of neonates born to SARS-CoV-2 infected mothers and increase the current knowledge on the perinatal consequences of COVID-19. Nineteen neonates were admitted to Tongji Hospital from January 31 to February 29, 2020. Their mothers were clinically diagnosed or laboratory-confirmed with COVID-19. We prospectively collected and analyzed data of mothers and infants. There are 19 neonates included in the research. Among them, 10 mothers were confirmed COVID-19 by positive SARS-CoV-2 RT-PCR in throat swab, and 9 mothers were clinically diagnosed with COVID-19. Delivery occurred in an isolation room and neonates were immediately separated from the mothers and isolated for at least 14 days. No fetal distress was found. Gestational age of the neonates was 38.6 AE 1.5 weeks, and average birth weight was 3293 AE 425 g. SARS-CoV-2 RT-PCR in throat swab, urine, and feces of all neonates were negative. SARS-CoV-2 RT-PCR in breast milk and amniotic fluid was negative too. None of the neonates developed clinical, radiologic, hematologic, or biochemical evidence of COVID-19. No vertical transmission of SARS-CoV-2 and no perinatal complications in the third trimester were found in our study. The delivery should occur in isolation and neonates should be separated from the infected mothers and care givers.

Interleukin-21 (IL-21 IntroductionIL-21 is produced mainly by activated CD4 ϩ T cells and regulates functions of T, B, natural killer (NK), and myeloid cells. IL-21 signaling requires the heterodimerization of the IL-21R and ␥ c cytoplasmic domains. 1,2 ␥ c is also shared by the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, and is mutated in patients with X-linked severe combined immunodeficiency (XSCID), a disease in which T and NK cells are absent and B cells are not functional. 3 Defective IL-21 signaling contributes to the intrinsic B-cell defect in XSCID. 4,5 Il21r Ϫ/Ϫ mice have diminished IgG1 but elevated IgE levels in response to antigen, whereas Il21r Ϫ/Ϫ /Il4 Ϫ/Ϫ double knock-out mice exhibit a pan-hypogammaglobulinemia similar to what is found in XSCID, indicating a cooperative role for IL-4 and IL-21 in Ig production. 4 Depending on the stimulation context, IL-21 can be proapoptotic for B cells [6][7][8] or can promote their differentiation to memory and plasma cells. 7,9 IL-21 can also potently augment T-cell proliferation as a comitogen 10 and cooperates with IL-7 or IL-15 to drive the proliferation of resting CD8 ϩ T cells. 11 It can also augment NK-cell activity [12][13][14][15][16] and exert actions on dendritic cells (DCs) 17 and monocytes/macrophages. 18 Furthermore, IL-21 has been reported to have antitumor effects in a range of model systems and has been implicated as contributing to autoimmunity. 5 However, relatively little is known regarding signaling by this important cytokine.Like other ␥ c -dependent cytokines, 19 IL-21 activates the Janus family tyrosine kinases, Jak1 and Jak3. 2,20 Whereas IL-2, IL-7, IL-9, and IL-15 primarily activate Stat5a and Stat5b, and IL-4 primarily activates Stat6, IL-21 has been reported to activate Stat1, Stat3, and Stat5, with preferential activation of Stat1 and Stat3. 1,2,[20][21][22] Phosphorylation of tyrosine residues in the cytoplasmic domain of cytokine receptors can regulate downstream signaling pathways by providing docking sites for Src homology 2 (SH2) and/or phosphotyrosine binding (PTB) domain-containing proteins, 23,24 including STAT proteins. We now investigate the role of IL-21R tyrosines in mediating IL-21-induced STAT protein activation, and we also demonstrate the importance of these tyrosines as well as the MAPK and PI 3-kinase (PI3K)/Akt pathways in IL-21-mediated proliferation. Materials and methods MiceMice lacking IL-21R 4 and Stat1 25 have been described. Mice lacking Stat3 in T cells (T-cell Stat3) were generated by breeding Stat3 f/f mice 26 to transgenic mice expressing Cre recombinase under the control of CD4 regulatory elements. 27 Mice lacking Stat1 and T-cell Stat3 were generated by standard interbreeding. 28 Mice were analyzed at 6 to 16 weeks of age. Experiments were performed under protocols approved by Animal Use and Care Committees at NIH and the NYU School of Medicine, in accord with NIH guidelines. In vitro cell cultureSplenocytes were prepared by pressing spleens through fine nylon screens. Erythrocytes were deple...