IFN-ε is a unique type I IFN that is not induced by pattern recognition response elements. IFN-ε is constitutively expressed in mucosal tissues, including the female genital mucosa. Although the direct antiviral activity of IFN-ε was thought to be weak compared with IFN-α, IFN-ε controls
Carley Tasker, Selvakumar Subbian, Pan Gao, Jennifer Couret, Carly Levine, Saleena Ghanny, Patricia Soteropoulos, Xilin Zhao, Nathaniel Landau, Wuyuan Lu, Theresa L. Chang
T cells that enter tumors are largely tolerized, but how that process is choreographed and how the ensuing “dysfunctional” tumor-infiltrating lymphocytes (TILs) are maintained are poorly understood and are difficult to assess in spontaneous disease. We exploited an autochthonous model of breast cancer for high-resolution imaging of the early and later stages of tumor residence to understand the relationships between cellular behaviors and cellular phenotypes. “Dysfunctional” differentiation began within the first days of tumor residence with an initial phase in which T cells arrest, largely on tumor-associated macrophages. Within 10 days, cellular motility increased and resembled a random walk, suggesting a relative absence of TCR signaling. We then studied the concurrent and apparently contradictory phenomenon that many of these cells express molecular markers of activation and were visualized undergoing active cell division. We found that whereas proliferation did not require ongoing TCR/ZAP70 signaling, instead this is driven in part by intratumoral IL-15 cytokine. Thus, TILs undergo sequential reprogramming by the tumor microenvironment and are actively retained, even while being antigen insensitive. We conclude that this program effectively fills the niche with ineffective yet cytokine-dependent TILs, and we propose that these might compete with new clones, when they arise.
Bijan Boldajipour, Amanda Nelson, Matthew F. Krummel
Rebecca A. Sosa, Ali Zarrinpar, Maura Rossetti, Charles R. Lassman, Bita V. Naini, Nakul Datta, Ping Rao, Nicholas Harre, Ying Zheng, Roberto Spreafico, Alexander Hoffmann, Ronald W. Busuttil, David W. Gjertson, Yuan Zhai, Jerzy W. Kupiec-Weglinski, Elaine F. Reed
Clinical monitoring of adoptive T cell transfer (ACT) utilizes serial blood analyses to discern T cell activity. While useful, these data are 1-dimensional and lack spatiotemporal information related to treatment efficacy or toxicity. We utilized a human genetic reporter, somatostatin receptor 2 (SSTR2), and PET, to quantitatively and longitudinally visualize whole-body T cell distribution and antitumor dynamics using a clinically approved radiotracer. Initial evaluations determined that SSTR2-expressing T cells were detectable at low densities with high sensitivity and specificity. SSTR2-based PET was applied to ACT of chimeric antigen receptor (CAR) T cells targeting intercellular adhesion molecule-1, which is overexpressed in anaplastic thyroid tumors. Timely CAR T cell infusions resulted in survival of tumor-bearing mice, while later infusions led to uniform death. Real-time PET imaging revealed biphasic T cell expansion and contraction at tumor sites among survivors, with peak tumor burden preceding peak T cell burden by several days. In contrast, nonsurvivors displayed unrelenting increases in tumor and T cell burden, indicating that tumor growth was outpacing T cell killing. Thus, longitudinal PET imaging of SSTR2-positive ACT dynamics enables prognostic, spatiotemporal monitoring with unprecedented clarity and detail to facilitate comprehensive therapy evaluation with potential for clinical translation.
Yogindra Vedvyas, Enda Shevlin, Marjan Zaman, Irene M. Min, Alejandro Amor-Coarasa, Spencer Park, Susan Park, Keon-Woo Kwon, Turner Smith, Yonghua Luo, Dohyun Kim, Young Kim, Benedict Law, Richard Ting, John Babich, Moonsoo M. Jin
BM-derived DC (BMDC) are powerful antigen-presenting cells. When loaded with immune complexes (IC), consisting of tumor antigens bound to antitumor antibody, BMDC induce powerful antitumor immunity in mice. However, attempts to employ this strategy clinically with either tumor-associated DC (TADC) or monocyte-derived DC (MoDC) have been disappointing. To investigate the basis for this phenomenon, we compared the response of BMDC, TADC, and MoDC to tumor IgG-IC. Our findings revealed, in both mice and humans, that upon exposure to IgG-IC, BMDC internalized the IC, increased costimulatory molecule expression, and stimulated autologous T cells. In contrast, TADC and, surprisingly, MoDC remained inert upon contact with IC due to dysfunctional signaling following engagement of Fcγ receptors. Such dysfunction is associated with elevated levels of the Src homology region 2 domain–containing phosphatase-1 (SHP-1) and phosphatases regulating Akt activation. Indeed, concomitant inhibition of both SHP-1 and phosphatases that regulate Akt activation conferred upon TADC and MoDC the capacity to take up and process IC and induce antitumor immunity in vivo. This work identifies the molecular checkpoints that govern activation of MoDC and TADC and their capacity to elicit T cell immunity.
Yaron Carmi, Tyler R. Prestwood, Matthew H. Spitzer, Ian L. Linde, Jonathan Chabon, Nathan E. Reticker-Flynn, Nupur Bhattacharya, Hong Zhang, Xiangyue Zhang, Pamela A. Basto, Bryan M. Burt, Michael N. Alonso, Edgar G. Engleman
CD4+ regulatory T cells (CD4Tregs) play a critical role in the maintenance of immune tolerance and prevention of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. IL-2 supports the proliferation and survival of CD4Tregs and previous studies have demonstrated that IL-2 induces selective expansion of CD4Tregs and improves clinical manifestations of chronic GVHD. However, mechanisms for selective activation of CD4Tregs and the effects of low-dose IL-2 on other immune cells are not well understood. Using mass cytometry, we demonstrate that low concentrations of IL-2 selectively induce STAT5 phosphorylation in Helios+ CD4Tregs and CD56brightCD16– NK cells in vitro. Preferential activation and expansion of Helios+ CD4Tregs and CD56brightCD16– NK cells was also demonstrated in patients with chronic GVHD receiving low-dose IL-2. With prolonged IL-2 treatment for 48 weeks, phenotypic changes were also observed in Helios– CD4Tregs. The effects of low-dose IL-2 therapy on conventional CD4+ T cells and CD8+ T cells were limited to increased expression of PD-1 on effector memory T cells. These studies reveal the selective effects of low-dose IL-2 therapy on Helios+ CD4Tregs and CD56bright NK cells that constitutively express high-affinity IL-2 receptors as well as the indirect effects of prolonged exposure to low concentrations of IL-2 in vivo.
Masahiro Hirakawa, Tiago Matos, Hongye Liu, John Koreth, Haesook T. Kim, Nicole E. Paul, Kazuyuki Murase, Jennifer Whangbo, Ana C. Alho, Sarah Nikiforow, Corey Cutler, Vincent T. Ho, Philippe Armand, Edwin P. Alyea, Joseph H. Antin, Bruce R. Blazar, Joao F. Lacerda, Robert J. Soiffer, Jerome Ritz
While respiratory failure in cystic fibrosis (CF) frequently associates with chronic infection by
Sladjana Skopelja, B. JoNell Hamilton, Jonathan D. Jones, Mei-Ling Yang, Mark Mamula, Alix Ashare, Alex H. Gifford, William F.C. Rigby
Recent clinical trials have demonstrated a clear survival advantage in advanced head and neck squamous cell carcinoma (HNSCC) patients treated with immune checkpoint blockade. These emerging results reveal that HNSCC is one of the most promising frontiers for immunotherapy research. However, further progress in head and neck immuno-oncology will require a detailed understanding of the immune infiltrative landscape found in these tumors. We leveraged transcriptome data from 280 tumors profiled by The Cancer Genome Atlas (TCGA) to comprehensively characterize the immune landscape of HNSCC in order to develop a rationale for immunotherapeutic strategies in HNSCC and guide clinical investigation. We find that both HPV+ and HPV– HNSCC tumors are among the most highly immune-infiltrated cancer types. Strikingly, HNSCC had the highest median Treg/CD8+ T cell ratio and the highest levels of CD56dim NK cell infiltration, in our pan-cancer analysis of the most immune-infiltrated tumors. CD8+ T cell infiltration and CD56dim NK cell infiltration each correlated with superior survival in HNSCC. Tumors harboring genetic smoking signatures had lower immune infiltration and were associated with poorer survival, suggesting these patients may benefit from immune agonist therapy. These findings illuminate the immune landscape of HPV+ and HPV– HNSCC. Additionally, this landscape provides a potentially novel rationale for investigation of agents targeting modulators of Tregs (e.g., CTLA-4, GITR, ICOS, IDO, and VEGFA) and NK cells (e.g., KIR, TIGIT, and 4-1BB) as adjuncts to anti–PD-1 in the treatment of advanced HNSCC.
Rajarsi Mandal, Yasin Şenbabaoğlu, Alexis Desrichard, Jonathan J. Havel, Martin G. Dalin, Nadeem Riaz, Ken-Wing Lee, Ian Ganly, A. Ari Hakimi, Timothy A. Chan, Luc G.T. Morris
Viral hepatitis remains a global health challenge despite recent progress in the development of more effective therapies. Although virus-specific CD8+ and CD4+ T cell responses are essential for viral clearance, it remains largely unknown what regulates T cell–mediated viral clearance. Thus, a better understanding of the regulation of anti-viral T cell immunity would be critical for the design of more effective therapies for viral hepatitis. Using a model of adenovirus-induced hepatitis, here we showed that adenoviral infection induced recruitment of Ly6Chi monocytes to the liver in a CCR2-dependent manner. These recruited Ly6Chi monocytes suppressed CD8+ and CD4+ T cell responses to adenoviral infection, leading to a delay in viral clearance. In vivo depletion of Ly6Chi monocytes markedly enhanced anti-viral T cell responses and promoted viral clearance. Mechanistically, we showed that induction of iNOS and the production of NO by Ly6Chi monocytes are critical for the suppression of T cell responses. In addition, a contact-dependent mechanism mediated by PD-1 and PD-L1 interaction is also required for T cell suppression by Ly6Chi monocytes. These findings suggest a critical role for Ly6Chi monocytes in the regulation of T cell immunity in viral hepatitis and may provide new insights into development of more effective therapies for treating viral hepatitis based on targeting the immunosuppressing monocytes.
Jiangao Zhu, Huiyao Chen, Xiaopei Huang, Songfu Jiang, Yiping Yang
Invasive pulmonary aspergillosis is a life-threatening mycosis that only affects patients with immunosuppression, chemotherapy-induced neutropenia, transplantation, or congenital immunodeficiency. We studied the clinical, genetic, histological, and immunological features of 2 unrelated patients without known immunodeficiency who developed extrapulmonary invasive aspergillosis at the ages of 8 and 18. One patient died at age 12 with progressive intra-abdominal aspergillosis. The other patient had presented with intra-abdominal candidiasis at age 9, and developed central nervous system aspergillosis at age 18 and intra-abdominal aspergillosis at age 25. Neither patient developed
Nikolaus Rieber, Roel P. Gazendam, Alexandra F. Freeman, Amy P. Hsu, Amanda L. Collar, Janyce A. Sugui, Rebecca A. Drummond, Chokechai Rongkavilit, Kevin Hoffman, Carolyn Henderson, Lily Clark, Markus Mezger, Muthulekha Swamydas, Maik Engeholm, Rebecca Schüle, Bettina Neumayer, Frank Ebel, Constantinos M. Mikelis, Stefania Pittaluga, Vinod K. Prasad, Anurag Singh, Joshua D. Milner, Kelli W. Williams, Jean K. Lim, Kyung J. Kwon-Chung, Steven M. Holland, Dominik Hartl, Taco W. Kuijpers, Michail S. Lionakis
Lymphangioleiomyomatosis (LAM) is a rare lung disease of women that leads to progressive cyst formation and accelerated loss of pulmonary function. Neoplastic smooth muscle cells from an unknown source metastasize to the lung and drive destructive remodeling. Given the role of NK cells in immune surveillance, we postulated that NK cell activating receptors and their cognate ligands are involved in LAM pathogenesis. We found that ligands for the NKG2D activating receptor UL-16 binding protein 2 (ULBP2) and ULBP3 are localized in cystic LAM lesions and pulmonary nodules. We found elevated soluble serum ULBP2 (mean = 575 pg/ml ± 142) in 50 of 100 subjects and ULBP3 in 30 of 100 (mean = 8,300 pg/ml ± 1,515) subjects. LAM patients had fewer circulating NKG2D+ NK cells and decreased NKG2D surface expression. Lung function decline was associated with soluble NKG2D ligand (sNKG2DL) detection. The greatest rate of decline forced expiratory volume in 1 second (FEV1, –124 ± 30 ml/year) in the 48 months after enrollment (NHLBI LAM Registry) occurred in patients expressing both ULBP2 and ULBP3, whereas patients with undetectable sNKG2DL levels had the lowest rate of FEV1 decline (–32.7 ± 10 ml/year). These data suggest a role for NK cells, sNKG2DL, and the innate immune system in LAM pathogenesis.
Andrew R. Osterburg, Rebecca L. Nelson, Benyamin Z. Yaniv, Rachel Foot, Walter R.F. Donica, Madison A. Nashu, Huan Liu, Kathryn A. Wikenheiser-Brokamp, Joel Moss, Nishant Gupta, Francis X. McCormack, Michael T. Borchers
Regulatory T cells (Tregs) play a crucial role in the maintenance of peripheral tolerance. Quantitative and/or qualitative defects in Tregs result in diseases such as autoimmunity, allergy, malignancy, and graft-versus-host disease (GVHD), a serious complication of allogeneic stem cell transplantation (SCT). We recently reported increased expression of autophagy-related genes (
Laëtitia Le Texier, Katie E. Lineburg, Benjamin Cao, Cameron McDonald-Hyman, Lucie Leveque-El Mouttie, Jemma Nicholls, Michelle Melino, Blessy C. Nalkurthi, Kylie A. Alexander, Bianca Teal, Stephen J. Blake, Fernando Souza-Fonseca-Guimaraes, Christian R. Engwerda, Rachel D. Kuns, Steven W. Lane, Michele Teng, Charis Teh, Daniel Gray, Andrew D. Clouston, Susan K. Nilsson, Bruce R. Blazar, Geoffrey R. Hill, Kelli P.A. MacDonald
Transcriptome profiles derived from the site of human disease have led to the identification of genes that contribute to pathogenesis, yet the complex mixture of cell types in these lesions has been an obstacle for defining specific mechanisms. Leprosy provides an outstanding model to study host defense and pathogenesis in a human infectious disease, given its clinical spectrum, which interrelates with the host immunologic and pathologic responses. Here, we investigated gene expression profiles derived from skin lesions for each clinical subtype of leprosy, analyzing gene coexpression modules by cell-type deconvolution. In lesions from tuberculoid leprosy patients, those with the self-limited form of the disease, dendritic cells were linked with
Megan S. Inkeles, Rosane M.B. Teles, Delila Pouldar, Priscila R. Andrade, Cressida A. Madigan, David Lopez, Mike Ambrose, Mahdad Noursadeghi, Euzenir N. Sarno, Thomas H. Rea, Maria T. Ochoa, M. Luisa Iruela-Arispe, William R. Swindell, Tom H.M. Ottenhoff, Annemieke Geluk, Barry R. Bloom, Matteo Pellegrini, Robert L. Modlin
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a pregnancy-related condition caused by maternal antibodies binding an alloantigen on fetal platelets. In most cases the alloantigen is formed by a single amino acid, integrin β3 Leu33, referred to as human platelet antigen–1a (HPA-1a). Production of anti–HPA-1a antibodies likely depends on CD4+ T cells that recognize the same alloantigen in complex with the HLA-DRA/DRB3*01:01 molecule. While this complex is well characterized, T cell recognition of it is not. Here, to examine the nature of antigen recognition by HPA-1a–specific T cells, we assayed native and synthetic variants of the integrin β3 peptide antigen for binding to DRA/DRB3*01:01-positive antigen-presenting cells and for T cell activation. We found that HPA-1a–specific T cells recognize non-allogeneic integrin β3 residues anchored to DRA/DRB3*01:01 by the allogeneic Leu33, which itself is not directly recognized by these T cells. Furthermore, these T cell responses are diverse, with different T cells depending on different residues for recognition. This represents a unique form of indirect allorecognition in which a non-allogeneic peptide sequence becomes immunogenic by stable anchoring to MHC by an allogeneic residue.
Maria Therese Ahlen, Anne Husebekk, Ida Løken Killie, Bjørn Skogen, Tor Brynjar Stuge
Genome-wide association studies of asthma have identified genetic variants in the
Erin D. Gordon, Joe Palandra, Agata Wesolowska-Andersen, Lando Ringel, Cydney L. Rios, Marrah E. Lachowicz-Scroggins, Louis Z. Sharp, Jamie L. Everman, Hannah J. MacLeod, Jae W. Lee, Robert J. Mason, Michael A. Matthay, Richard T. Sheldon, Michael C. Peters, Karl H. Nocka, John V. Fahy, Max A. Seibold
In carcinogen-driven cancers, a high mutational burden results in neoepitopes that can be recognized immunologically. Such carcinogen-induced tumors may evade this immune response through “immunoediting,” whereby tumors adapt to immune pressure and escape T cell–mediated killing. Many tumors lack a high neoepitope burden, and it remains unclear whether immunoediting occurs in such cases. Here, we evaluated T cell immunity in an autochthonous mouse model of pancreatic cancer and found a low mutational burden, absence of predicted neoepitopes derived from tumor mutations, and resistance to checkpoint immunotherapy. Spontaneous tumor progression was identical in the presence or absence of T cells. Moreover, tumors arising in T cell–depleted mice grew unchecked in immune-competent hosts. However, introduction of the neoantigen ovalbumin (OVA) led to tumor rejection and T cell memory, but this did not occur in OVA immune-tolerant mice. Thus, immunoediting does not occur in this mouse model — a likely consequence, not a cause, of absent neoepitopes. Because many human tumors also have a low missense mutational load and minimal neoepitope burden, our findings have clinical implications for the design of immunotherapy for patients with such tumors.
Rebecca A. Evans, Mark S. Diamond, Andrew J. Rech, Timothy Chao, Max W. Richardson, Jeffrey H. Lin, David L. Bajor, Katelyn T. Byrne, Ben Z. Stanger, James L. Riley, Nune Markosyan, Rafael Winograd, Robert H. Vonderheide
Patrick H. Lizotte, Elena V. Ivanova, Mark M. Awad, Robert E. Jones, Lauren Keogh, Hongye Liu, Ruben Dries, Christina Almonte, Grit S. Herter-Sprie, Abigail Santos, Nora B. Feeney, Cloud P. Paweletz, Meghana M. Kulkarni, Adam J. Bass, Anil K. Rustgi, Guo-Cheng Yuan, Donald W. Kufe, Pasi A. Jänne, Peter S. Hammerman, Lynette M. Sholl, F. Stephen Hodi, William G. Richards, Raphael Bueno, Jessie M. English, Mark A. Bittinger, Kwok-Kin Wong
Fibrosis is a shared end-stage pathway to lung, liver, and heart failure. In the ocular mucosa (conjunctiva), fibrosis leads to blindness in trachoma, pemphigoid, and allergy. The indirect fibrogenic role of DCs via T cell activation and inflammatory cell recruitment is well documented. However, here we demonstrate that DCs can directly induce fibrosis. In the mouse model of allergic eye disease (AED), classical CD11b+ DCs in the ocular mucosa showed increased activity of aldehyde dehydrogenase (ALDH), the enzyme required for retinoic acid synthesis. In vitro, CD11b+ DC–derived ALDH was associated with 9-
Sarah D. Ahadome, Rose Mathew, Nancy J. Reyes, Priyatham S. Mettu, Scott W. Cousins, Virginia L. Calder, Daniel R. Saban
Systemic sclerosis (SSc) is a potentially fatal autoimmune disorder with limited therapeutic options. Sclerodermatous graft versus host disease (sclGvHD), induced by transfer of B10.D2 splenocytes into BALB/c
Katia Urso, David Alvarez, Viviana Cremasco, Kelly Tsang, Angelo Grauel, Robert Lafyatis, Ulrich H. von Andrian, Joerg Ermann, Antonios O. Aliprantis
Following the advent of molecular assays that measure T cell receptor excision circles (TRECs) present in recent thymic emigrants, it has been conclusively shown that thymopoiesis persists in most adults, but that functional output decreases with age, influencing the maintenance of a diverse and functional T cell receptor (TCR) repertoire. Space flight has been shown to result in a variety of phenotypic and functional changes in human T cells and in the reactivation of latent viruses. While space flight has been shown to influence thymic architecture in rodents, thymopoiesis has not previously been assessed in astronauts. Here, we assessed thymopoiesis longitudinally over a 1-year period prior to and after long-term space flight (median duration, 184 days) in 16 astronauts. While preflight assessments of thymopoiesis remained quite stable in individual astronauts, we detected significant suppression of thymopoiesis in all subjects upon return from space flight. We also found significant increases in urine and plasma levels of endogenous glucocorticoids coincident with the suppression of thymopoiesis. The glucocorticoid induction and thymopoiesis suppression were transient, and they normalized shortly after return to Earth. This is the first report to our knowledge to prospectively demonstrate a significant change in thymopoiesis in healthy individuals in association with a defined physiologic emotional and physical stress event. These results suggest that suppression of thymopoiesis has the potential to influence the maintenance of the TCR repertoire during extended space travel. Further studies of thymopoiesis and endogenous glucocorticoids in other stress states, including illness, are warranted.
Cara L. Benjamin, Raymond P. Stowe, Lisa St. John, Clarence F. Sams, Satish K. Mehta, Brian E. Crucian, Duane L. Pierson, Krishna V. Komanduri
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