Clinical trials of biologic therapies in type 1 diabetes (T1D) aim to mitigate autoimmune destruction of pancreatic beta cells through immune perturbation and serve as resources to elucidate immunological mechanisms in health and disease. In the T1DAL trial of alefacept (LFA3-Ig) in recent onset T1D, endogenous insulin production was preserved in 30% of subjects for two years post-therapy. Given our previous findings linking exhausted CD8 T cells to beneficial response in T1D trials, we applied unbiased analyses to sorted CD8 T cells to evaluate their potential role in T1DAL. Using RNA-seq, we found that greater insulin C-peptide preservation was associated with a module of activation- and exhaustion-associated genes. This signature was dissected into two distinct CD8 memory populations through correlation with clustered cytometry data. Both populations were hypo-proliferative, shared expanded TCR junctions, and expressed exhaustion-associated markers including TIGIT and KLRG1. The populations were distinguished by reciprocal expression of CD8 T and NK cell markers (GZMB, CD57 and inhibitory KIR genes), versus T cell activation and differentiation markers (PD1 and CD28). These findings support previous evidence linking exhausted CD8 T cells to successful immune interventions for T1D, while suggesting multiple inhibitory mechanisms can promote this beneficial cell state.
Kirsten E. Diggins, Elisavet Serti, Virginia S. Muir, Mario G. Rosasco, TingTing Lu, Elisa Balmas, Gerald T. Nepom, S. Alice Long, Peter S. Linsley
Aberrant activation of NLRP3 inflammasome has been implicated in a variety of human inflammatory diseases, however currently no pharmacological NLRP3 inhibitor has been approved in clinic. In this study, we showed that echinatin, the ingredient of the traditional herbal medicine licorice, effectively suppresses the activation of NLRP3 inflammasome in vitro and in vivo. Further investigation revealed that echinatin exerts its inhibitory effect on NLRP3 inflammasome by binding to heat-shock protein 90 (HSP90), inhibiting its ATPase activity, and disrupting the association between the cochaperone SGT1 and HSP90-NLRP3. Importantly, in vivo experiments demonstrated that administration of echinatin obviously inhibits NLRP3 inflammasome activation and ameliorates LPS-induced septic shock and DSS-induced colitis in mice. Moreover, echinatin exerted favorable pharmacological effects on liver inflammation and fibrosis in mouse model of non-alcoholic steatohepatitis (NASH). Collectively, our study identified echinatin as a novel inhibitor of NLRP3 inflammasome and may be developed as a potentially therapeutic approach for the treatment of NLRP3-driven diseases.
Guang Xu, Shubin Fu, Xiaoyan Zhan, Zhilei Wang, Ping Zhang, Wei Shi, Nan Qin, Yuanyuan Chen, Chunyu Wang, Ming Niu, Yuming Guo, Jia-bo Wang, Zhaofang Bai, Xiaohe Xiao
Tumor antigen-specific CD4 T cells accumulate at tumor sites evoking their involvement in antitumor effector functions in situ. Contrarily to CD8 cytotoxic T-lymphocyte exhaustion, that of CD4 T cells remains poorly appreciated. Here, using phenotypic, transcriptomic and functional approaches, we characterized CD4 T-cell exhaustion in head and neck, cervical and ovarian cancer patients. We identified a CD4 tumor-infiltrating lymphocyte (TIL) population, defined by high PD-1 and CD39 expression, which contained high proportions of cytokine-producing cells, although the quantity of cytokines produced by these cells was low evoking an exhausted state. Terminal exhaustion of CD4 TILs was instated regardless of TIM-3 expression suggesting divergence with CD8 T-cell exhaustion. ScRNA-Seq and further phenotypic analyses uncovered, however, similarities with the CD8 T-cell exhaustion program. In particular, PD-1hiCD39+ CD4 TILs expressed the exhaustion transcription factor TOX and the chemokine CXCL13 and were tumor antigen-specific. In vitro, PD-1 blockade enhanced CD4 TIL activation, as evidenced by increased CD154 expression and cytokine secretion, leading to improved dendritic cell maturation and consequently to higher tumor-specific CD8 T-cell proliferation. Our data identify CD4 TIL exhaustion as a player of responsiveness to immune checkpoint blockade.
Camille-Charlotte Balança, Anna Salvioni, Clara-Maria Scarlata, Marie Michelas, Carlos Martinez-Gomez, Carlos Gomez-Roca, Victor Sarradin, Marie Tosolini, Carine Valle, Frédéric Pont, Gwénaël Ferron, Laurence Gladieff, Sébastien Vergez, Agnès Dupret-Bories, Eliane Mery, Philippe Rochaix, Jean-Jacques Fournié, Jean-Pierre Delord, Christel Devaud, Alejandra Martinez, Maha Ayyoub
Individuals younger than 6 months of age are at significant risk from influenza virus infection; however, there is currently no vaccine approved for this age group. Influenza virus neuraminidase (NA) has emerged as a potential additional target for vaccine strategies. In this study, we sought to understand the ability of newborns to mount an antibody response to NA. Here we employed a nonhuman primate model, given the similarities to humans in immune system and development. We measured antibody to NA following infection with an H1N1 virus or following vaccination and challenge. Administration of an inactivated virus vaccine was not capable of eliciting detectable NA-specific antibody, even in the presence of adjuvants previously shown to increase total virus-specific IgG. However, both naive and vaccinated newborns generated a NA-specific antibody response following virus infection. Interestingly, the presence of the vaccine-induced response did not prevent generation of systemic antibody to NA following challenge, although the respiratory response was reduced in a significant portion of newborns. These findings are the first, to our knowledge, to evaluate the newborn response to the influenza NA protein as well as the impact of previous vaccination on generation of these antibodies following virus infection.
Patrick K. Shultz, Kali F. Crofts, Beth C. Holbrook, Martha A. Alexander-Miller
Immune dysfunction is an important factor driving mortality and adverse outcomes after trauma but remains poorly understood, especially at cellular level. To deconvolute trauma-induced immune response, we applied single-cell RNA sequencing to circulating and bone marrow mononuclear cells in injured mice and circulating mononuclear cells in trauma patients. In mice, the greatest changes in gene expression were seen in monocytes across both compartments. After systemic injury, the gene expression pattern of monocytes markedly deviated from steady state with corresponding changes in critical transcription factors (TFs), which can be traced back to myeloid progenitors. These changes were largely recapitulated in human single-cell analysis. We generalized the major changes in human CD14+ monocytes into six signatures, which further defined two trauma patient subtypes (SG1 vs. SG2) identified in the whole blood leukocyte transcriptome in the initial 12h after injury. Compared with SG2, SG1 patients exhibited delayed recovery, more severe organ dysfunction and a higher incidence of infection and non-infectious complications. The two patient subtypes were also recapitulated in burn and sepsis patients, revealing a shared pattern of immune response across critical illness. Our data will be broadly useful to further explore the immune response to inflammatory diseases and critical illness.
Tianmeng Chen, Matthew J. Delano, Kong Chen, Jason L. Sperry, Rami A. Namas, Ashley J. Lamparello, Meihong Deng, Julia Conroy, Lyle L. Moldawer, Philip A. Efron, Patricia A. Loughran, Christopher W. Seymour, Derek C. Angus, Yoram Vodovotz, Wei Chen, Timothy R. Billiar
Transient partial remission, a period of low insulin requirement experienced by most patients soon after diagnosis has been associated with mechanisms of immune regulation. A better understanding of such natural mechanisms of immune regulation might identify new targets for immunotherapies that reverse T1D. In this study, using Cox model multivariate analysis we validate our previous findings that patients (n = 84) with the highest frequency of CD4+ CD25+CD127hi (127-hi) cells at diagnosis experience the longest partial remission and we show that the 127-hi cell population is a mix of Th1- and Th2-type cells with a significant bias towards anti-inflammatory Th2-type cells. In addition, we extend these findings to show that patients with the highest frequency of 127-hi cells at diagnosis are significantly more likely to maintain beta-cell function. Moreover, in patients treated with Alefacept in the TIDAL clinical trial, the probability of responding favorably to the anti-inflammatory drug was significantly higher in those with a higher frequency of 127-hi cells at diagnosis than those with a lower 127-hi cell frequency. These data are consistent with the hypothesis that 127-hi cells maintain an anti-inflammatory environment that is permissive for partial remission, beta-cell survival and response to anti-inflammatory immunotherapy.
Aditi Narsale, Breanna Lam, Rosita Moya, TingTing Lu, Alessandra Mandelli, Irene Gotuzzo, Benedetta Pessina, Gian Maria Giamporcaro, Rhonda Geoffrey, Kerry Buchanan, Mark Harris, Anne-Sophie Bergot, Ranjeny Thomas, Martin J. Hessner, Manuela Battaglia, Elisavet Serti, Joanna D. Davies
Current treatments for pneumonia (PNA) are focused on the pathogens. Mortality from PNA-induced acute lung injury (PNA-ALI) remains high, underscoring the need for additional therapeutic targets. Clinical and experimental evidence exists for potential sex differences in PNA survival, with males having higher mortality. In a model of severe pneumococcal PNA, when compared to males, age-matched female mice exhibited enhanced resolution characterized with decreased alveolar and lung inflammation and increased numbers of Regulatory T cells (Tregs). Recognizing the critical role of Tregs in lung injury resolution, we evaluated if improved outcomes in females were due to estradiol (E2) effects on Treg biology. E2 promoted Treg suppressive phenotype in vitro and resolution of PNA in vivo. Systemic rescue administration of E2 promoted resolution of PNA in males independent of lung bacterial clearance. E2 augmented Treg expression of Foxp3, CD25 and GATA3, an effect that required ERb, and not ERa signaling. Importantly, the in vivo therapeutic effects of E2 were lost in Treg depleted mice (Foxp3DTR). Adoptive transfer of ex vivo E2-treated Tregs rescued S. pneumoniae-induce PNA-ALI, a salutary effect that required Treg ERβ expression. E2-ERβ was required for Tregs to control macrophage pro-inflammatory responses. Our findings support the therapeutic role for E2 in promoting resolution of lung inflammation after PNA via ERβ Tregs.
Ye Xiong, Qiong Zhong, Tsvi Palmer, Alison Benner, Lan Wang, Karthik Suresh, Rachel Damico, Franco R. D'Alessio
Esophageal Adenocarcinoma (EAC) develops from Barrett’s Esophagus (BE), a chronic inflammatory state that can progress through a series of transformative dysplastic states before tumor development. While molecular and genetic changes of EAC tumors have been studied, immune microenvironment changes during Barrett’s progression to EAC remain poorly understood. In this study, we identify potential immunologic changes which can occur during BE to EAC progression. RNA Sequencing (RNA-Seq) analysis on tissue samples from EAC patients undergoing surgical resection demonstrated that a subset of chemokines and cytokines, most notably IL-6 and IL-8, increased during BE progression to EAC. xCell deconvolution analysis investigating immune cell population changes demonstrated that the largest changes in expression during BE progression occurred in M2 macrophages, pro B-cells, and eosinophils. Multiplex immunohistochemical staining of tissue microarrays showed increased immune cell populations during Barrett’s progression to high grade dysplasia. In contrast, EAC tumor sections were relatively immune poor, with a rise in PD-L1 expression and loss of CD8+ T-cells. These data demonstrate the EAC microenvironment is characterized by poor cytotoxic effector cell infiltration and increased immune inhibitory signaling. These findings suggest an immune suppressive microenvironment, highlighting the need for further studies to explore immune modulatory therapy in EAC.
Kiran H. Lagisetty, Dyke P. McEwen, Derek J. Nancarrow, Johnathon G. Schiebel, Daysha Ferrer-Torres, Dipankar Ray, Timothy L. Frankel, Jules Lin, Andrew C. Chang, Laura A. Kresty, David G. Beer
Immune and inflammatory responses to SARS-CoV-2 contribute to disease severity of COVID-19. However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity, and assessed type-I IFN-, type-II IFN-, and NF-κB-dependent whole blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and non-hematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type-I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients’ first samples revealed 12 biomarkers (CCL2, IL-15, sST2, NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and two additional biomarkers (lactoferrin, CXCL9) that were significantly associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome.
Michael S. Abers, Ottavia M. Delmonte, Emily E. Ricotta, Jonathan Fintzi, Danielle Fink, Adriana A. de Jesus, Kol A. Zarember, Sara Alehashemi, Vasileios Oikonomou, Jigar V. Desai, Scott W. Canna, Bita Shakoory, Kerry Dobbs, Luisa Imberti, Alessandra Sottini, Eugenia Quiros-Roldan, Francesco Castelli, Camillo Rossi, Duilio Brugnoni, Andrea Biondi, Laura R. Bettini, Mariella D’Angio’, Paolo Bonfanti, Riccardo Castagnoli, Daniela Montagna, Amelia Licari, Gian Luigi Marseglia, Emily Gliniewicz, Elana R. Shaw, Dana Kahle, Andre T. Rastegar, Michael A Stack, Katherine Myint-Hpu, Susan L. Levinson, Mark J. DiNubile, Daniel W. Chertow, Peter Burbelo, Jeffrey I. Cohen, Katherine R. Calvo, John S. Tsang, Helen C. Su, John I. Gallin, Douglas B. Kuhns, Raphaela Goldbach-Mansky, Michail S Lionakis, Luigi D Notarangelo
Glioblastoma multiforme (GBM) is a fatal human cancer in part because GBM stem cells are resistant to therapy and recurrence is inevitable. Previously, we demonstrated Zika virus (ZIKV) targets GBM stem cells and prevents death of mice with gliomas. Here, we evaluated the immunological basis of ZIKV-mediated protection against GBM. Introduction of ZIKV into the brain tumor increases recruitment of CD8+ T and myeloid cells to the tumor microenvironment. CD8+ T cells are required for ZIKV-dependent tumor clearance, as survival benefits are lost with CD8+ T cell depletion. Moreover, while anti-PD1 antibody therapy alone moderately improves tumor survival, when co-administered with ZIKV, survival increases. ZIKV-mediated tumor clearance also results in durable protection against syngeneic tumor re-challenge, which also depends on CD8+ T cells. To address safety concerns, we generated an immune-sensitized ZIKV strain, which is effective alone or in combination with immunotherapy. Thus, oncolytic ZIKV treatment can be leveraged by immunotherapies, which may prompt combination treatment paradigms for adult GBM patients.
Sharmila Nair, Luciano Mazzoccoli, Arijita Jash, Jennifer Govero, Sachendra S. Bais, Tong Hu, Camila R. Fontes-Garfias, Chao Shan, Hideho Okada, Sujan Shresta, Jeremy N. Rich, Pei-Yong Shi, Michael S. Diamond, Milan G. Chheda
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