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Mounting evidence suggests that aberrations in immune-inflammatory pathways contribute to the pathophysiology of major depressive disorder (MDD), and individuals with MDD may have elevated levels of predominantly pro-inflammatory cytokines and C-reactive protein. In addition, previous meta-analyses suggest that antidepressant drug treatment may decrease peripheral levels of interleukin-1 beta (IL-1β) and IL-6. Recently, several new studies examining the effect of antidepressants on these cytokines have been published, and so we performed an updated meta-analysis of studies that measured peripheral levels of cytokines and chemokines during antidepressant treatment in patients with MDD. The PubMed/MEDLINE, EMBASE, and PsycInfo databases were searched from inception through March 9, 2017. Forty-five studies met inclusion criteria (N = 1517). Peripheral levels of IL-6, tumor necrosis factor-alpha (TNF-α), IL-1β, IL-10, IL-2, IL-4, interferon-γ, IL-8, the C-C motif ligand 2 chemokine (CCL-2), CCL-3, IL-1 receptor antagonist, IL-13, IL-17, IL-5, IL-7, and the soluble IL-2 receptor were measured in at least three datasets and thus were meta-analyzed. Antidepressant treatment significantly decreased peripheral levels of IL-6 (Hedges g = −0.454, P <0.001), TNF-α (g = −0.202, P = 0.015), IL-10 (g = −0.566, P = 0.012), and CCL-2 (g = −1.502, P = 0.006). These findings indicate that antidepressants decrease several markers of peripheral inflammation. However, this meta-analysis did not provide evidence that reductions in peripheral inflammation are associated with antidepressant treatment response although few studies provided separate data for treatment responders and non-responders.

Synthetic receptor signalling has the potential to endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumours, including the need for conditioning chemotherapy 1 , 2 . Here we designed chimeric receptors that have an orthogonal IL-2 receptor extracellular domain (ECD) fused with the intracellular domain (ICD) of receptors for common γ-chain (γ c ) cytokines IL-4, IL-7, IL-9 and IL-21 such that the orthogonal IL-2 cytokine elicits the corresponding γ c cytokine signal. Of these, T cells that signal through the chimeric orthogonal IL-2Rβ-ECD–IL-9R-ICD (o9R) are distinguished by the concomitant activation of STAT1, STAT3 and STAT5 and assume characteristics of stem cell memory and effector T cells. Compared to o2R T cells, o9R T cells have superior anti-tumour efficacy in two recalcitrant syngeneic mouse solid tumour models of melanoma and pancreatic cancer and are effective even in the absence of conditioning lymphodepletion. Therefore, by repurposing IL-9R signalling using a chimeric orthogonal cytokine receptor, T cells gain new functions, and this results in improved anti-tumour activity for hard-to-treat solid tumours. Synthetic chimeric orthogonal IL-2 receptors that incorporate the intracellular domain of receptors for other γ-chain cytokines such as IL-9 can reroute orthogonal signalling and alter the phenotype of T cells to improve anti-tumour responses.

We describe a de novo computational approach for designing proteins that recapitulate the binding sites of natural cytokines, but are otherwise unrelated in topology or amino acid sequence. We use this strategy to design mimics of the central immune cytokine interleukin-2 (IL-2) that bind to the IL-2 receptor βγ c heterodimer (IL-2Rβγ c ) but have no binding site for IL-2Rα (also called CD25) or IL-15Rα (also known as CD215). The designs are hyper-stable, bind human and mouse IL-2Rβγ c with higher affinity than the natural cytokines, and elicit downstream cell signalling independently of IL-2Rα and IL-15Rα. Crystal structures of the optimized design neoleukin-2/15 (Neo-2/15), both alone and in complex with IL-2Rβγ c , are very similar to the designed model. Neo-2/15 has superior therapeutic activity to IL-2 in mouse models of melanoma and colon cancer, with reduced toxicity and undetectable immunogenicity. Our strategy for building hyper-stable de novo mimetics could be applied generally to signalling proteins, enabling the creation of superior therapeutic candidates. A hyper-stable de novo protein mimic of interleukin-2 computationally designed to not interact with a regulatory T-cell specific receptor subunit has improved therapeutic activity in mouse models of melanoma and colon cancer.

Background COVID-19 is highly contagious, and the crude mortality rate could reach 49% in critical patients. Inflammation concerns on disease progression. This study analyzed blood inflammation indicators among mild, severe and critical patients, helping to identify severe or critical patients early. Methods In this cross-sectional study, 100 patients were included and divided into mild, severe or critical groups according to disease condition. Correlation of peripheral blood inflammation-related indicators with disease criticality was analyzed. Cut-off values for critically ill patients were speculated through the ROC curve. Results Significantly, disease severity was associated with age ( R  = -0.564, P  < 0.001), interleukin-2 receptor (IL2R) ( R  = -0.534, P  < 0.001), interleukin-6 (IL-6) ( R  = -0.535, P  < 0.001), interleukin-8 (IL-8) ( R  = -0.308, P  < 0.001), interleukin-10 (IL-10) ( R  = -0.422, P  < 0.001), tumor necrosis factor α (TNFα) ( R  = -0.322, P  < 0.001), C-reactive protein (CRP) ( R  = -0.604, P  < 0.001), ferroprotein ( R  = -0.508, P  < 0.001), procalcitonin ( R  = -0.650, P  < 0.001), white cell counts (WBC) ( R  = -0.54, P  < 0.001), lymphocyte counts (LC) ( R  = 0.56, P  < 0.001), neutrophil count (NC) ( R  = -0.585, P  < 0.001) and eosinophil counts (EC) ( R  = 0.299, P  < 0.001). With IL2R > 793.5 U/mL or CRP > 30.7 ng/mL, the progress of COVID-19 to critical stage should be closely observed and possibly prevented. Conclusions Inflammation is closely related to severity of COVID-19, and IL-6 and TNFα might be promising therapeutic targets.

Preclinical studies of the T cell growth factor activity of IL-2 resulted in this cytokine becoming the first immunotherapy to be approved nearly 30 years ago by the US Food and Drug Administration for the treatment of cancer. Since then, we have learnt the important role of IL-2 in regulating tolerance through regulatory T cells (Treg cells) besides promoting immunity through its action on effector T cells and memory T cells. Another pivotal event in the history of IL-2 research was solving the crystal structure of IL-2 bound to its tripartite receptor, which spurred the development of cell type-selective engineered IL-2 products. These new IL-2 analogues target Treg cells to counteract the dysregulated immune system in the context of autoimmunity and inflammatory disorders or target effector T cells, memory T cells and natural killer cells to enhance their antitumour responses. IL-2 biologics have proven to be effective in preclinical studies and clinical assessment of some is now underway. These studies will soon reveal whether engineered IL-2 biologics are truly capable of harnessing the IL-2–IL-2 receptor pathway as effective monotherapies or combination therapies for autoimmunity and cancer.Here, Malek and colleagues describe the multiple ways in which IL-2 biologics have been engineered to preferentially target regulatory T cells or effector T cells, memory T cells and natural killer cells to correct dysregulated or insufficient immune responses in the settings of autoimmunity or cancer.

Key Points The common cytokine receptor γ-chain (γ c ) family of cytokines consists of interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21, each of which is a short-chain four α-helical bundle type I cytokine. Mutations in the gene encoding γ c ( IL2RG ) in humans result in X-linked severe combined immunodeficiency, which is characterized by a marked defect in the development of T and natural killer (NK) cells and functional defects of B cells; in mice, deletion of this gene is characterized by the absence of B, T and NK cells. γ c family cytokines and the related cytokine thymic stromal lymphopoietin (TSLP) have distinct effects on the regulation of survival and proliferation of T cells. IL-2 and TSLP increase the proliferation and/or survival of effector T cells, whereas IL-7, IL-15 and TSLP are survival factors for naive and memory αβ T cells, as well as γδ T cells. In addition, the combination of IL-15 and IL-21 increases the proliferation and decreases the apoptosis of CD8 + T cells. As well as the direct effects of γ c family cytokines and TSLP on the homeostasis of T cells, they also have indirect effects on T cells through their regulation of dendritic cell (DC) functions. IL-15 and TSLP induce the up-regulation of expression of co-stimulatory molecules and increased presentation of antigen on DCs, whereas IL-7 and IL-21 suppress the maturation of DCs. Although IL-2 is an important factor for the development and function of regulatory T (T Reg ) cells, the lack of IL-2, IL-2Rα or IL-2Rβ does not alter the expression of forkhead box P3 (FOXP3) or result in a complete loss of T Reg cells. By contrast, STAT5 activation is sufficient to increase the number of CD4 + CD25 + T Reg cells even when IL-2-induced signalling is defective, which shows that STAT5A and STAT5B are crucial factors downstream of IL-2R and indicates that other factors that activate the STAT5 pathway might also contribute to T Reg cell development and could partially compensate when IL-2-induced signalling is defective. Indeed, IL-7, IL-15 and TSLP also contribute to T Reg cell development and function. In the primary response to antigen, naive CD4 + T cells differentiate to distinct polarized subsets, including T helper 1 (T H 1), T H 2, T H 17 and T follicular helper (T FH ) cells. Recent studies show that IL-2 and IL-4 are both required for the efficient induction of T H 2 cells and that IL-21 can promote the differentiation of T H 17 cells and T FH cells. In addition to their contributions to T H cell differentiation, γ c cytokines also contribute to the generation and activity of cytotoxic CD8 + T cells, with IL-2, IL-15 and IL-21 increasing the cytolytic activity of CD8 + T cells during priming and increasing their antitumour immunity. The actions of γ c cytokines have clinical relevance, and modulation of their effects has implications for the treatment of cancer, autoimmunity, allergy and immunodeficiency. Administration of IL-2, IL-15 and IL-21 has antitumour effects; treatment with IL-2, IL-7 and IL-15 could be used in immunodeficiency disorders; blocking of IL-4, IL-9 and TSLP can decrease allergic symptoms; and neutralization of IL-21 could prevent and/or ameliorate several autoimmune diseases. In this Review, the authors discuss the central roles of the common cytokine receptor γ-chain (γ c ) family of cytokines, as well as the related cytokine TSLP, in the homeostasis, proliferation and differentiation of various T cell subsets and describe how these cytokines could be exploited for therapeutic purposes. Common cytokine receptor γ-chain (γ c ) family cytokines have crucial roles in the development, proliferation, survival and differentiation of multiple cell lineages of both the innate and adaptive immune systems. In this Review, we focus on our current understanding of the distinct and overlapping effects of interleukin-2 (IL-2), IL-7, IL-9, IL-15 and IL-21, as well as the IL-7-related cytokine thymic stromal lymphopoietin (TSLP), on the survival and proliferation of conventional αβ T cells, γδ T cells and regulatory T cells. This knowledge potentially allows for the therapeutic manipulation of immune responses for the treatment of cancer, autoimmunity, allergic diseases and immunodeficiency, as well as for vaccine development.

Background: Coronavirus disease 2019 (COVID-2019), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide epidemic and claimed millions of lives. Accumulating evidence suggests that cytokines storms are closely associated to COVID-19 severity and death. Here, we aimed to explore the key factors related to COVID-19 severity and death, especially in terms of the male patients and those in western countries. Methods: To clarify whether inflammatory cytokines have role in COVID-19 severity and death, we systematically searched PubMed, Embase, Cochrane library and Web of Science to identify related studies with the keywords “COVID-19″ and “cytokines”. The data were measured as the mean with 95% confidence interval (CI) by Review Manager 5.3 software. The risk of bias was assessed for each study using appropriate checklists. Results: We preliminarily screened 13,468 studies from the databases. A total of 77 articles with 13,468 patients were ultimately included in our study. The serum levels of cytokines such as interleukin-6 (IL-6), IL-10, interleukin-2 receptor (IL-2R), tumor necrosis factor (TNF)-α, IL-1β, IL-4, IL-8 and IL-17 were higher in the severity or death group. Notably, we also found that the circulating levels of IL-6, IL-10, IL-2R and TNF-α were significantly different between males and females. The serum levels of IL-6, IL-10, IL-2R and TNF-α were much higher in males than in females, which implies that the increased mortality and severity in males was partly due to the higher level of these cytokines. Moreover, we found that in the severe and non-survivor groups, European patients had elevated levels of IL-6 compared with Asian patients. Conclusion: These large-scale data demonstrated that the circulating levels of IL-6, IL-10, IL-2R, IL-1β, IL-4, IL-8 and IL-17 are potential risk factors for severity and high mortality in COVID-19. Simultaneously, the upregulation of these cytokines may be driving factors for the sex and region predisposition.

Interleukin-2 (IL-2) is an important cytokine that helps T cells destroy tumors and virus-infected cells. IL-2 has great therapeutic promise but is limited by toxic side effects and its capacity to both activate and repress immune responses. Sockolosky et al. set out to improve IL-2–based immunotherapy by engineering synthetic IL-2–receptor pairs (i.e., IL-2 and its receptor, IL-2R) (see the Perspective by Mackall). Engineered complexes transmitted IL-2 signals but only interacted with each other and not with endogenous IL-2/IL-2R. Treatment of mice with IL-2 improved the ability of engineered T cells to reject tumors with no obvious side effects. This type of approach may provide a way to mitigate toxicities associated with some cytokine-based immunotherapies. Science , this issue p. 1037 ; see also p. 990 Engineered cytokines are able to improve immunotherapy in mouse tumor models. Interleukin-2 (IL-2) is a cytokine required for effector T cell expansion, survival, and function, especially for engineered T cells in adoptive cell immunotherapy, but its pleiotropy leads to simultaneous stimulation and suppression of immune responses as well as systemic toxicity, limiting its therapeutic use. We engineered IL-2 cytokine-receptor orthogonal ( ortho ) pairs that interact with one another, transmitting native IL-2 signals, but do not interact with their natural cytokine and receptor counterparts. Introduction of ortho IL-2Rβ into T cells enabled the selective cellular targeting of ortho IL-2 to engineered CD4 + and CD8 + T cells in vitro and in vivo, with limited off-target effects and negligible toxicity. Ortho IL-2 pairs were efficacious in a preclinical mouse cancer model of adoptive cell therapy and may therefore represent a synthetic approach to achieving selective potentiation of engineered cells.

The cytokine receptor IL-2R is essential for the development of T reg cells; therefore, it has been difficult to separate this from its role in the suppressive function of T reg cells. Rudensky and colleagues use various genetic systems to show that capture of IL-2 by IL-2R is important for suppression of CD8 + T cells but not that of CD4 + T cells. Regulatory T cells (T reg cells), which have abundant expression of the interleukin 2 receptor (IL-2R), are reliant on IL-2 produced by activated T cells. This feature indicates a key role for a simple network based on the consumption of IL-2 by T reg cells in their suppressor function. However, congenital deficiency in IL-2R results in reduced expression of the T reg cell lineage–specification factor Foxp3, which has confounded experimental efforts to understand the role of IL-2R expression and signaling in the suppressor function of T reg cells. Using genetic gain- and loss-of-function approaches, we found that capture of IL-2 was dispensable for the control of CD4 + T cells but was important for limiting the activation of CD8 + T cells, and that IL-2R-dependent activation of the transcription factor STAT5 had an essential role in the suppressor function of T reg cells separable from signaling via the T cell antigen receptor.

Expansion of antigen-experienced CD8 + T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer 1 . Interleukin-2 (IL-2) acts as a key regulator of CD8 + cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability 2 , 3 . Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE 2 ), a known negative regulator of immune response in the tumour microenvironment 4 , 5 , is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8 + TILs via the PGE 2 receptors EP2 and EP4. Mechanistically, PGE 2 inhibits IL-2 sensing in TILs by downregulating the IL-2Rγ c chain, resulting in defective assembly of IL-2Rβ–IL2Rγ c membrane dimers. This results in impaired IL-2–mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE 2  signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE 2 in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential. Prostaglandin E2 from the tumour microenvironment impairs interleukin-2 sensing by tumour-infiltrating lymphocytes, restricting proliferative response and promoting T cell death via metabolic impairment and ferroptosis.