2'3'-cGAMP is known as a non-classical 2nd messenger and small immune modulator that possesses potent anti-tumor and antiviral activities through stimulating STING-mediated signaling pathway. However, its function in regulating type 2 immune responses remains unknown. We sought to determine a role of STING activation by 2'3'-cGAMP in type 2 inflammatory reactions in multiple mouse models of eosinophilic asthma. We discovered that 2'3'-cGAMP administration strongly attenuated type 2 lung immunopathology and airway hyperresponsiveness (AHR) induced by IL-33 and a fungal allergen, A. flavus. Mechanistically, upon the respiratory delivery, 2'3'-cGAMP was mainly internalized by alveolar macrophages, in which it activated the STING-IRF3-IFN-I signaling axis to induce the production of inhibitory factors containing IFNα, which blocked the IL-33-mediated activation of group 2 innate lymphoid cells (ILC2) in vivo. We further demonstrated that 2'3'-cGAMP directly suppressed the proliferation and function of both human and mouse ILC2 in vitro. Taken together, our findings suggest that STING activation by 2'3'-cGAMP in alveolar macrophages and ILC2 cells can negatively regulate type 2 immune responses, implying that the respiratory delivery of 2'3'-cGAMP might be further developed as an alternative strategy for treating type 2 immunopathologic diseases such as eosinophilic asthma.
Li She, Gema D. Barrera, Liping Yan, Hamad Hazzaa Alanazi, Edward G. Brooks, Peter H. Dube, Yilun Sun, Hong Zan, Daniel P. Chupp, Nu Zhang, Xin Zhang, Yong Liu, Xiao-Dong Li
Antiretroviral therapies (ART) abrogate HIV replication; however, infection persists as long-lived reservoirs of infected cells with integrated proviruses, which re-seed replication if ART is interrupted. A central tenet of our current understanding of this persistence is that infected cells are shielded from immune recognition and elimination through a lack of antigen expression from proviruses. Efforts to cure HIV infection have therefore focused on reactivating latent proviruses to enable immune-mediated clearance, but these have yet to succeed in reducing viral reservoirs. Here, we revisited the question of whether HIV reservoirs are predominately immunologically silent from a new angle: by querying the dynamics of HIV-specific T-cell responses over long-term ART for evidence of ongoing recognition of HIV-infected cells. In longitudinal assessments, we show that the rates of change in persisting HIV Nef-specific responses, but not responses to other HIV gene products, were associated with residual frequencies of infected cells. These Nef-specific responses were highly stable over time, and disproportionately exhibited a cytotoxic, effector functional profile, indicative of recent in vivo recognition of HIV antigens. These results indicate substantial visibility of the HIV-infected cells to T-cells on stable ART, presenting both opportunities and challenges for the development of therapeutic approaches to curing infection.
Eva M. Stevenson, Adam R. Ward, Ronald Truong, Allison S. Thomas, Szu-Han Huang, Thomas R. Dilling, Sandra Terry, John K. Bui, Talia M. Mota, Ali Danesh, Guinevere Q. Lee, Andrea Gramatica, Pragya Khadka, Winiffer D. Conce Alberto, Rajesh T. Gandhi, Deborah K. McMahon, Christina M. Lalama, Ronald J. Bosch, Bernard J. Macatangay, Joshua C. Cyktor, Joseph J. Eron, John W. Mellors, R. Brad Jones
Hepatitis B virus (HBV)-specific CD8+ T cells fail to acquire effector functions after priming in the liver, but the molecular basis for the dysfunctionality is poorly understood. By comparing the gene expression profile of intrahepatically primed, dysfunctional HBV-specific CD8+ T cells with that of systemically primed, functional effector counterparts, we found that the expression of interferon-stimulated genes (ISGs) is selectively suppressed in the dysfunctional CD8+ T cells. The ISG suppression was associated with impaired phosphorylation of STAT1 in response to IFNα treatment. Importantly, a strong induction of type interferons (IFN-Is) in the liver facilitated the functional differentiation of intrahepatically primed HBV-specific CD8+ T cells in association with the restoration of ISGs expression in the T cells. These results suggest that intrahepatic priming suppresses IFN-I signaling in CD8+ T cells, which may contribute to the dysfunctionality. The data also suggest a therapeutic value of the robust induction of intrahepatic IFN-Is for the treatment of chronic HBV infection.
Keigo Kawashima, Masanori Isogawa, Masaya Onishi, Ian Baudi, Satoru Saito, Atsushi Nakajima, Takashi Fujita, Yasuhito Tanaka
Interleukin-10 (IL-10) is a critical cytokine used by immune cells to suppress inflammation. Paradoxically, immune cell-derived IL-10 can drive insulin resistance in obesity by suppressing adipocyte energy expenditure and thermogenesis. However, the source of IL-10 necessary for the suppression of adipocyte thermogenesis is unknown. We show here that CD4+ Foxp3+ regulatory T cells (Tregs) are a significant source of IL-10, and that Treg-derived IL-10 can suppress adipocyte beiging. Unexpectedly, Treg-specific loss of IL-10 resulted in increased insulin sensitivity and reduced obesity in high fat diet (HFD)-fed male mice. Mechanistically, we determined that Treg-specific loss of the transcription factor Blimp-1, a driver of IL-10 expression by Tregs, phenocopied the Treg-specific IL-10-deficient mice. Loss of Blimp-1 expression in Tregs resulted in reduced ST2+, KLRG1+, IL-10-secreting Tregs, particularly in the white adipose tissue. Blimp-1-deficient mice were protected from glucose intolerance, insulin resistance and diet-induced obesity (DIO), through increased white adipose tissue browning. Taken together, our data show that Blimp-1-regulated IL-10 secretion by Tregs represses white adipose tissue beiging to maintain adipose tissue homeostasis.
Lisa Y. Beppu, Raja Mooli, Xiaoyao Qu, Giovanni J. Marrero, Christopher A. Finley, Allen N. Fooks, Zackary P. Mullen, Adolfo B. Frias Jr., Ian J. Sipula, Bingxian Xie, Katherine E. Helfrich, Simon C. Watkins, Amanda C. Poholek, Sadeesh K. Ramakrishnan, Michael J. Jurczak, Louise M. D'Cruz
Although many HIV cure strategies seek to expand HIV-specific CD8+ T cells to control the virus, all are likely to fail if cellular exhaustion is not prevented. A loss in stem-like memory properties (i.e., the ability to proliferate and generate secondary effector cells) is a key feature of exhaustion; little is known, however, about how these properties are regulated in human virus-specific CD8+ T cells. We found that virus-specific CD8+ T cells from humans and non-human primates naturally controlling HIV/SIV infection express more of the transcription factor, TCF-1, than non-controllers. HIV-specific CD8+ T cell TCF-1 expression correlated with memory marker expression and expansion capacity and declined with antigenic stimulation. CRISPR-Cas9 editing of TCF-1 in human primary T cells demonstrated a direct role in regulating expansion capacity. Collectively, these data suggest that TCF-1 contributes to the regulation of the stem-like memory property of secondary expansion capacity of HIV-specific CD8+ T cells, and they provide a rationale for exploring the enhancement of this pathway in T cell-based therapeutic strategies for HIV.
Rachel L. Rutishauser, Christian Deo T. Deguit, Joseph Hiatt, Franziska Blaeschke, Theodore L. Roth, Lynn Wang, Kyle A. Raymond, Carly E. Starke, Joseph C. Mudd, Wenxuan Chen, Carolyn P. Smullin, Rodrigo Matus-Nicodemos, Rebecca Hoh, Melissa R. Krone, Frederick M. Hecht, Christopher D. Pilcher, Jeffrey N. Martin, Richard A. Koup, Daniel C. Douek, Jason M. Brenchley, Rafick-Pierre Sékaly, Satish K. Pillai, Alexander Marson, Steven G. Deeks, Joseph M. McCune, Peter W. Hunt
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
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