SOCS1 links cytokine signaling to p53 and senescence.

SOCS1 is lost in many human tumors, but its tumor suppression activities are not well understood. We report that SOCS1 is required for transcriptional activity, DNA binding, and serine 15 phosphorylation of p53 in the context of STAT5 signaling. In agreement, inactivation of SOCS1 disabled p53-dependent senescence in response to oncogenic STAT5A and radiation-induced apoptosis in T cells. In addition, SOCS1 was sufficient to induce p53-dependent senescence in fibroblasts. The mechanism of activation of p53 by SOCS1 involved a direct interaction between the SH2 domain of SOCS1 and the N-terminal transactivation domain of p53, while the C-terminal domain of SOCS1 containing the SOCS Box mediated interaction with the DNA damage-regulated kinases ATM/ATR. Also, SOCS1 colocalized with ATM at DNA damage foci induced by oncogenic STAT5A. Collectively, these results add another component to the p53 and DNA damage networks and reveal a mechanism by which SOCS1 functions as a tumor suppressor.

Regulation of cytokine-driven functional differentiation of CD8 T cells by suppressor of cytokine signaling 1 controls autoimmunity and preserves their proliferative capacity toward foreign antigens.

We have previously shown that naive CD8 T cells exposed to IL-7 or IL-15 in the presence of IL-21 undergo Ag-independent proliferation with concomitant increase in TCR sensitivity. In this study, we examined whether CD8 T cells that accumulate in suppressor of cytokine signaling 1 (SOCS1)-deficient mice because of increased IL-15 signaling in vivo would respond to an autoantigen expressed at a very low level using a mouse model of autoimmune diabetes. In this model, P14 TCR transgenic CD8 T cells (P14 cells) adoptively transferred to rat insulin promoter-glycoprotein (RIP-GP) mice, which express the cognate Ag in the islets, do not induce diabetes unless the donor cells are stimulated by exogenous Ag. Surprisingly, SOCS1-deficient P14 cells, which expanded robustly following IL-15 stimulation, proliferated poorly in response to Ag and failed to cause diabetes in RIP-GP mice. SOCS1-deficient CD8 T cells expressing a polyclonal TCR repertoire also showed defective expansion following in vivo Ag stimulation. Notwithstanding the Ag-specific proliferation defect, SOCS1-null P14 cells produced IFN-gamma and displayed potent cytolytic activity upon Ag stimulation, suggesting that SOCS1-null CD8 T cells underwent cytokine-driven functional differentiation that selectively compromised their proliferative response to Ag but not to cytokines. Cytokine-driven homeostatic expansion in lymphopenic RIP-GP mice allowed SOCS1-null, but not wild-type, P14 cells to exert their pathogenic potential even without Ag stimulation. These findings suggest that by attenuating cytokine-driven proliferation and functional differentiation, SOCS1 not only controls the pathogenicity of autoreactive cells but also preserves the ability of CD8 T cells to proliferate in response to Ags.

Mobile App-Based Remote Patient Monitoring in Acute Medical Conditions: Prospective Feasibility Study Exploring Digital Health Solutions on Clinical Workload During the COVID Crisis.

BACKGROUND: Digital remote patient monitoring can add value to virtual wards; this has become more apparent in the context of the COVID-19 pandemic. Health care providers are overwhelmed, resulting in clinical teams spread more thinly. We aimed to assess the impact of introducing an app-based remote patient monitoring system (Huma Therapeutics) on a clinician's workload in the context of a COVID-19-specific virtual ward. OBJECTIVE: This prospective feasibility study aimed to evaluate the health economic effects (in terms of clinical workload) of a mobile app on a telephone-based virtual ward used in the monitoring of patients with COVID-19 who are clinically ready for discharge from the hospital. METHODS: A prospective feasibility study was carried out over 1 month where clinician workload was monitored, and full-time equivalents savings were determined. An NHS hospital repurposed a telephone-based respiratory virtual ward for COVID-19. Patients with COVID-19 in the amber zone (according to the National Health Service definition) were monitored for 14 days postdischarge to help identify deteriorating patients earlier. A smartphone-based app was introduced to monitor data points submitted by the patients via communication over telephone calls. We then comparatively evaluated the clinical workload between patients monitored by telephone only (cohort 1) with those monitored via mobile app and telephone (cohort 2). RESULTS: In all, 56 patients were enrolled in the app-based virtual ward (cohort 2). Digital remote patient monitoring resulted in a reduction in the number of phone calls from a mean total of 9 calls to 4 calls over the monitoring period. There was no change in the mean duration of phone calls (8.5 minutes) and no reports of readmission or mortality. These results equate to a mean saving of 47.60 working hours. Moreover, it translates to 3.30 fewer full-time equivalents (raw phone call data), resulting in 1.1 fewer full-time equivalents required to monitor 100 patients when adjusted for time spent reviewing app data. Individual clinicians spent an average of 10.9 minutes per day reviewing data. CONCLUSIONS: Smartphone-based remote patient monitoring technologies may offer tangible reductions in clinician workload at a time when service is severely strained. In this small-scale pilot study, we demonstrated the economic and operational impact that digital remote patient monitoring technology can have in improving working efficiency and reducing operational costs. Although this particular RPM solution was deployed for the COVID-19 pandemic, it may set a precedent for wider utilization of digital, remote patient monitoring solutions in other clinical scenarios where increased care delivery efficiency is sought.

Increased antigen responsiveness of naive CD8 T cells exposed to IL-7 and IL-21 is associated with decreased CD5 expression.

Exposure of naive CD8 T cells to the synergistic combination of interleukin (IL)-7 and IL-21 enables them to respond strongly to subsequent antigen stimulation. Mechanisms underlying the increased antigen responsiveness of such cytokine-primed CD8 T cells remain unknown. In this study, we showed that a brief exposure of <24 h to IL-7 and IL-21 is sufficient enough to sensitize naive P14 T-cell receptor (TCR) transgenic CD8 T cells to respond to limiting quantities of antigen, resulting in increased proliferation, interferon-gamma secretion and antigen-specific cytolytic activity. Cytokine-induced increase in TCR responsiveness occurs even in the absence of costimulatory signals. Cytokine priming upregulates the expression of the gamma(c) chain and increases IL-2 production after antigen stimulation, thus enhancing autocrine stimulation. Notably, cytokine priming induces a rapid and profound downmodulation of CD5, implicated in the negative regulation of TCR signaling, by induction of the transcriptional repressor E47. These findings show that increased antigen responsiveness of cytokine-primed CD8 T cells results from the modulation of multiple cell-surface molecules, which influence cytokine receptor and TCR signaling.

Cytokine synergy in antigen-independent activation and priming of naive CD8+ T lymphocytes.

Activation of naive T cells by antigen requires signaling via the T-cell receptor (TCR) and co-stimulatory receptors. However, in response to homeostatic pressure, T lymphocytes undergo cytokine-driven proliferation without overt antigen stimulation. Homeostatic expansion is more pronounced in the CD8+ T-cell compartment, with memory CD8+ T cells showing intense proliferation resulting from increased responsiveness to IL-15. On the other hand, naive CD8+ T cells require IL-7 and MHC-I to undergo homeostatic expansion, implying the requirement for a basal level of TCR signaling. Probably because of this strict requirement for MHC, earlier reports on antigen-independent stimulation of naive human CD8+ T cells by inflammatory cytokines did not receive much attention. Recently, we and others have shown that naive murine CD8+ T cells undergo proliferation following synergistic simulation by inflammatory cytokines. Such cytokine-driven, antigen-independent activation also "sensitizes" or "primes" naive CD8+ T cells, enabling them to respond robustly to limiting concentrations of cognate antigens, produce effector cytokines abundantly, and display potent cytolytic activity. We propose that cytokine synergy, which induces antigen-independent activation and priming of naive CD8+ T cells, may significantly contribute to the transition from innate to adaptive immune response and to inadvertent activation of autoreactive CD8+ T cells.

Regulation of IL-21 signaling by suppressor of cytokine signaling-1 (SOCS1) in CD8(+) T lymphocytes.

Mice lacking the gene for suppressor of cytokine signaling 1 (SOCS1) show defective homeostasis of T lymphocytes due to accumulation of CD8(+) T cells, resulting at least partly from dysregulated IL-15 signaling. IL-15 alone does not stimulate proliferation of naïve CD8 T cells, but can synergize with IL-21 to induce proliferation, suggesting a potential role for IL-21 in the defective homeostasis of CD8(+) T lymphocytes in SOCS1(-/-) mice. Since IL-21 strongly induced SOCS1 mRNA in CD8(+) T cells, we investigated whether SOCS1 regulates their response to IL-21. CD8(+) T cells isolated from SOCS1-deficient mice proliferated vigorously in response to IL-21+IL-15. In CD8(+) T lymphocytes expressing transgenic TCR, IL-21+IL-7 provided a stronger stimulus to naïve cells whereas IL-15+IL-21 potently stimulated memory cells. Compared to truly naïve or memory cells, SOCS1(-/-) H-Y TCR(+) CD8(+) T cells displayed CD44(lo)Ly6C(hi)CD122(int)CD127(lo) partial memory phenotype and exhibited stronger response to IL-15+IL-21 than truly naïve cells. In SOCS1(-/-) CD8(+) T cells, IL-21 caused greater reduction in IL-15 threshold for activation in a dose-dependent manner. SOCS1 deficiency did not modulate IL-21Ralpha expression or sensitivity to IL-21, but delayed the loss of IL-21-induced phospho-STAT3 signal. These results show that SOCS1 is a critical regulator of IL-21 signaling in CD8(+) T cells, and support the notion that sustained IL-21 signaling might also contribute to the aberrant T cell homeostasis in SOCS1-deficient mice.

Human papillomavirus vaccines: key factors in planning cost-effective vaccination programs.

Prophylactic HPV vaccines hold tremendous potential for reducing cervical and non-cervical HPV-related disease burden worldwide. To maximize on this potential, policy officials will need to carefully consider available evidence, existing uncertainties and the cost-effectiveness of mass HPV vaccination programs in the context of their respective nations and/or regions. Proper harmonization of primary prevention strategies with secondary prevention efforts will also be important. Decisions following such considerations may ultimately depend on programmatic objectives, infrastructure and available resources. Continued research and surveillance surrounding HPV vaccination will be essential for filling current knowledge gaps, and forcing ongoing reconsiderations of selected immunization strategies.

Temporal trends and sex differences in pulmonary vein isolation for patients with atrial fibrillation.

BACKGROUND: Indications for pulmonary vein isolation for the treatment of atrial fibrillation (AF) have expanded over the years. OBJECTIVE: We aimed to describe trends in demographic and clinical characteristics of patients undergoing ablation, with a particular focus on sex differences. METHODS: Patients who underwent first AF ablation between 2003 and 2012 were identified within an AF cohort by using Quebec administrative databases. Descriptive statistics and multivariable analysis were used to examine sex differences and temporal trends in demographic and clinical characteristics, as well as independent predictors of the ablation procedure. RESULTS: A total of 2438 of 173,689 patients in the AF cohort underwent AF ablation. In the span of 10 years, the rate of AF ablation increased from 8.5 to 57.2 per million persons-an almost 7-fold increase. Patients undergoing ablation were younger than patients in the general AF cohort (57.4 ± 12.2 years vs 75.3 ± 12.0 years) and had fewer baseline comorbidities (56.7% vs 88.4%). Representing 42.9% of the general AF cohort, the annual proportion of women in the AF ablation cohort has not surpassed 30%, and men had a higher likelihood of undergoing ablation than did women (odds ratio 1.54; 95% confidence interval 1.40-1.69). Over the decade of observation, there were slight increases in patient age, comorbidities, and CHADS2 score, some of which reached clinical significance for men and/or women. CONCLUSION: The uptake of AF ablation over 10 years has expanded, with an increasingly greater number of older patients and with increased presence of comorbidities; however, there has been no increase in the relatively low proportion of women undergoing AF ablation.

Increased generation of CD8 single positive cells in SOCS1-deficient thymus does not proportionately increase their export.

Mice lacking suppressor of cytokine signaling 1 (SOCS1) accumulate CD8(+) T lymphocytes in the thymus and in the periphery. Whereas IL-7 and IL-15 promote the generation of CD8 single positive (SP) thymocytes, IL-15 drives the expansion of CD8 T cells in the periphery. Here, we investigated whether increased production of CD8 SP thymocytes is accompanied by their increased export in SOCS1-deficient mice. In vivo labeling with bromodeoxyuridine showed increased cycling of CD8 SP thymocytes in SOCS1-deficient mice. However, SOCS1-deficient thymi contained increased proportion of CD24(lo)CD69(lo) SP thymocytes as well as increased expression of Qa-2 in both CD4 and CD8 SP compartments. Analysis of recent thymic emigrants (RTE) following intrathymic labeling with fluorescein isothiocyanate revealed less efficient export of CD8 RTEs from SOCS1-deficient thymi and comparable CD4:CD8 ratio among RTEs in SOCS1-null and control mice. These findings show that the rate of export of CD8 SP thymocytes is not proportional to their generation in SOCS1-deficient thymi and suggest the existence of homeostatic mechanisms controlling the egress of CD8 T cells.

Antigen-nonspecific activation of CD8+ T lymphocytes by cytokines: relevance to immunity, autoimmunity, and cancer.

Development of T lymphocytes and their survival in the periphery are dependent on signals emanating from cytokine receptors as well as the T cell antigen receptor (TCR). These two signaling pathways play distinct and complementary roles at various stages of T cell development, maturation, survival, activation and differentiation. During immune response to foreign antigens initiated by TCR signaling, cytokines play a key role in the expansion of activated T cells. Even though the initial activation of T cells occurs via the TCR, this requirement can be overcome under certain circumstances. During lymphopenia, cytokines trigger memory CD8(+) T cells to undergo antigen non-specific homeostatic expansion, whereas naïve CD8(+) T cells require both cytokines and TCR signaling. Recent reports show certain combinations of cytokines can induce proliferation and effector functions of naïve CD8(+) T cells without concomitant stimulation via the TCR. While such antigen non-specific stimulation of naïve T cells might significantly boost the adaptive immune response, it could also have an undesirable effect of triggering potentially autoreactive cells. Understanding the mechanisms and the regulation of cytokine-driven stimulation of naïve CD8(+) T cells may lead to novel strategies of intervention for autoimmune diseases. On the other hand, in vitro expansion of naïve CD8(+) T cells by certain combinations of cytokines could be used to generate tumor-specific cells with ideal properties for cellular immunotherapy of cancer.

IL-6, in synergy with IL-7 or IL-15, stimulates TCR-independent proliferation and functional differentiation of CD8+ T lymphocytes.

Recent reports have shown that IL-21, in synergy with IL-15, stimulates proliferation of CD8(+) T lymphocytes in the absence of signaling via the TCR. In this study, we show that IL-6, which induces phosphorylation of STAT3 similarly to IL-21, also can stimulate proliferation of CD8(+) T cells in synergy with IL-7 or IL-15. IL-6 displays a stronger synergy with IL-7 than with IL-15 to stimulate naive CD8(+) T cells. Concomitant stimulation by IL-6 or IL-21 augments phosphorylation and DNA-binding activity of STAT5 induced by IL-7 or IL-15. Like IL-21, IL-6 reduces the TCR signaling threshold required to stimulate CD8(+) T cells. Prior culture of P14 TCR transgenic CD8 T cells with IL-6 or IL-21 in the presence of IL-7 or IL-15 augments their proliferation and cytolytic activity upon subsequent stimulation by Ag. Furthermore, cytokine stimulation induces quantitatively and qualitatively distinct phenotypic changes on CD8(+) T cells compared with those induced by TCR signaling. We propose that the ability of IL-6 to induce TCR-independent activation of CD8(+) T cells in synergy with IL-7 or IL-15 may play an important role in the transition from innate to adaptive immunity.

Suppressor of cytokine signaling 1 stringently regulates distinct functions of IL-7 and IL-15 in vivo during T lymphocyte development and homeostasis.

SOCS1(-/-) mice accumulate within the thymus and periphery CD8(+) lymphocytes that express memory cell markers and display heightened in vitro responses to common gamma-chain cytokines. To investigate whether dysregulated homeostasis of T lymphocytes and acquisition of memory phenotype by CD8(+) cells in SOCS1(-/-) mice were mediated by IL-7 and/or IL-15 in vivo, we have generated SOCS1(-/-)IL-7(-/-), SOCS1(-/-)IL-15(-/-) and SOCS1(-/-)IL-7(-/-)IL-15(-/-) mice. We observed that in mice lacking SOCS1, either IL-7 or IL-15 skewed thymocyte development toward CD8 lineage, whereas IL-15 is the principal mediator of dysregulated homeostasis in the periphery. Homeostatic proliferation of SOCS1(-/-) CD8(+) lymphocytes in Rag1(-/-), Rag1(-/-)IL-7(-/-), Rag1(-/-)IL-15(-/-), and Rag1(-/-)IL-7(-/-)IL-15(-/-) mice showed that SOCS1 deficiency did not overcome the requirement for IL-7 and IL-15 to sustain homeostatic expansion. Differential expression of memory phenotype markers CD44, CD122, and Ly6C by SOCS1(-/-)IL-15(-/-) CD8(+) lymphocytes suggest that multiple signals contributed to the memory cell differentiation program. To address whether increased IL-15 responsiveness of SOCS1(-/-) CD8(+) lymphocytes required prior TCR sensitization, we generated SOCS1(-/-) H-Y TCR transgenic (Tg) mice. Using female SOCS1(-/-) H-Y TCR(tg) mice in Rag1(+/+) and Rag1(-/-) backgrounds, we show that acquisition of the memory phenotype by SOCS1-deficient CD8(+) lymphocytes did not require prior antigenic stimulation, but required the presence of activated T cells. SOCS1 deficiency accelerated the maturation of CD8 single-positive thymocytes expressing Tg TCR, but did not compromise negative selection in HY-TCR(tg) males. Our findings illustrate distinct functions for IL-7 and IL-15 in T lymphocyte development and homeostasis, and stringent regulation of these processes by SOCS1.