Commentary
Abstract
Tumor-infiltrating lymphocytes (TILs) contain substantial numbers of CD4+ T cells mediating pro- and antitumor functions. While CD4+ Tregs are well characterized and known to promote tumor immune evasion, the fingerprint of CD4+ Th cells that recognizes tumor antigens and serves to restrict disease progression has remained poorly discriminated. In this issue of the JCI, Duhen et al. analyzed tumors from patients with head and neck squamous cell carcinoma or colon carcinoma and identified a unique programmed cell death 1–positive, ICOS1-positive (PD-1+ICOS1+) subpopulation of CD4+ TILs highly enriched for the ability to recognize tumor-associated antigens. These cells localized proximally to MHC II+ antigen-presenting cells and CD8+ T cells within tumors, where they appeared to proliferate and function almost exclusively as Th cells. These potentially therapeutic Th cells can be monitored for patient prognosis and are expected to have substantial utility in developing personalized adoptive cell– and vaccine-based immunotherapeutic approaches for improving patient outcomes.
Authors
Jessica N. Filderman, Walter J. Storkus
Abstract
Fibrodysplasia ossificans progressiva (FOP) is an ultrarare, debilitating disease in which heterotopic bone is formed in certain soft tissues. A gain-of-function variant in the cytoplasmic domain of the activin A receptor type I (ACVR1) exists in all patients with FOP. Strikingly, these FOP-causing variants imbue a neofunction to ACVR1 — the ability to recognize activin A as an agonist with bone morphogenic protein–like signaling that leads to heterotopic ossification (HO). These findings are supported by the efficacy of anti–activin A antibodies in preventing HO in FOP mice. This surprising story continues in companion papers in this issue of the JCI. Aykul et al. and Lees-Shepard et al. independently found that antibodies against ACVR1, which were being developed as potential therapeutics for FOP, instead caused HO in FOP mice. While this unexpected finding may be the clinical final act for such antibodies, it provides another twist in the unique and evolving FOP story.
Authors
Michael T. Collins
Abstract
Approximately half of patients with hematologic malignancy who are treated with allogeneic hematopoietic stem cell transplantation (alloHCT) experience graft-versus-host disease (GVHD), which has high mortality rates despite immunosuppressive therapy. IL-12 is known to drive donor T cells toward an inflammatory Th1 lineage in GVHD, but other mechanisms also promote pathological Th1 alloimmune responses. In this issue of the JCI, Dwyer et al. report on their use of transgenic mice and alloHCT models of GVHD to demonstrate that IL-33 acts directly on donor T cells to increase Tbet expression independently of IL-12. Notably, IL-33 amplified T cell receptor–signaling pathways and inhibited production of regulatory molecules. These findings firmly establish IL-33 as an important costimulatory molecule for Th1 cells during GVHD and provide a target for reducing GVHD, especially in the gastrointestinal (GI) tract, where damage drives mortality.
Authors
James Ferrara, Mariano Prado-Acosta
Abstract
HIV infection results in defective CD8+ T cell functions that are incompletely resolved by antiretroviral therapy (ART) except in natural controllers, who have functional CD8+ T cells associated with viral control. In this issue of the JCI, Perdomo-Celis et al. demonstrated that targeting the Wnt/transcription factor T cell factor 1 (Wnt/TCF-1) pathway in dysfunctional CD8+ T cells led to gains in stemness phenotype, metabolic quiescence, survival potential, response to homeostatic γ-chain cytokines, and antiviral capacities, similar to profiles of functional CD8+ T cells in natural controllers. Although reprogramming might not sufficiently reverse the imprinted dysfunction of CD8+ T cells in HIV infection, these findings outline the Wnt/TCF-1 pathway as a potential target to reprogram dysfunctional CD8+ T cells in efforts to achieve HIV remission.
Authors
Hiroshi Takata, Lydie Trautmann
Abstract
Although aging and lung injury are linked to the development of idiopathic pulmonary fibrosis (IPF), the underlying pathognomonic processes predisposing to fibrotic lesions remain largely unknown. A deficiency in the ability of type 2 alveolar epithelial cell (AEC2) progenitors to regenerate and repair the epithelia has been proposed as a critical factor. In this issue of the JCI, Liang et al. identify a deficiency in the zinc transporter SLC39A8 (ZIP8) in AEC2s and in the subsequent activation of the sirtuin SIRT1 that predisposes to decreased AEC2 renewal capacity and enhanced lung fibrosis in both IPF and aging lungs. Interestingly, the authors demonstrate the efficacy of modulating dietary zinc levels, suggesting the need for clinical trials to evaluate the therapeutic potential of dietary supplementation and the development of pharmacological modulation of the Zn/ZIP8/SIRT1 axis for treatment.
Authors
Paul S. Foster, Hock L. Tay, Brian G. Oliver
Abstract
Since researchers first began to uncover the mechanisms underlying allogeneic transplantation, the focus has been on T cells. T cells are a major instigator of graft-versus-host disease (GVHD). The clear association between GVHD occurrence and subsequent reduction in relapse supported concentrating on T cells as the masterminds behind graft-versus-tumor (GVT) effects. Recently, an alternative mediator of GVT has taken center stage: natural killer (NK) cells. Part of the appeal of NK cells is their potential to provide antitumor immunity without GVHD. Donor lymphocyte infusion has been the predominant treatment of relapse after allogeneic transplant, but the mix of lymphocytes includes CD8+ T cells and, consequently, a substantial risk for GVHD. In this issue of the JCI, Shapiro and colleagues developed an adoptive NK cell transfer platform to treat relapse after haploidentical allogeneic transplant. The study demonstrated safety, sought to determine resistance mechanisms, and provided avenues for future research.
Authors
Shannon R. McCurdy
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a major health concern that often associates with obesity and diabetes. Fatty liver is usually a benign condition, yet a fraction of individuals progress to severe forms of liver damage, including nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Elevated sterol regulatory element–binding protein–driven (SREBP-driven) hepatocyte lipid synthesis is associated with NAFLD in humans and mice. In this issue of the JCI, Kawamura, Matsushita, et al. evaluated the role of SREBP-dependent lipid synthesis in the development of NAFLD, NASH, and HCC in the phosphatase and tensin homolog–knockout (PTEN-knockout) NASH model. Deletion of the gene encoding SREBP cleavage–activating protein (SCAP) from the liver resulted in decreased hepatic lipids, as expected. However, SCAP deletion accelerated progression to more severe liver damage, including NASH and HCC. This study provides a note of caution for those pursuing de novo fat biosynthesis as a therapeutic intervention in human NASH.
Authors
Timothy F. Osborne, Peter J. Espenshade
Abstract
The loss of skeletal muscle mass and size, or muscle atrophy, is a common human experience, linked to disability, for which there are no widely accepted pharmacological therapies. Piezo1 is a mechanosensitive cation channel that opens upon alteration of the plasma membrane lipid bilayer, such as through increased membrane tension. In this issue of the JCI, Hirata et al. identified Piezo1 and its downstream effectors, Krüppel-like factor 15 (KLF15) and interleukin-6 (IL-6), as an important signaling pathway in a murine model of disuse atrophy. Through genetic and pharmacological modulation of the pathway, the authors demonstrated that immobilization resulted in downregulation of Piezo1 and basal intracellular calcium concentration ([Ca2+]i), increasing expression of Klf15 and its downstream target Il6 and thereby inducing muscle atrophy. Piezo1 has been considered a therapeutic target for diverse disorders, including atherosclerosis and kidney fibrosis, and with this publication should now also be considered a viable target for disuse atrophy.
Authors
Ravi Jagasia, Kathryn R. Wagner
Abstract
Bile acids modulate cell functions in health and disease, however, the mechanisms underlying their actions on neoplastic cells in the gastrointestinal (GI) tract remain largely unknown. In this issue of the JCI, Noto et al. comprehensively analyzed how interactions between Helicobacter pylori infection, iron deficiency, and bile acids modulate gastric inflammation and carcinogenesis. The investigators used sophisticated models, including INS-GAS mice with elevated serum gastrin and gastric acid secretion, in which H. pylori infection mimics human disease progression, to show that selected bile acids potentiated the carcinogenic effects of H. pylori infection and iron depletion. This elegant work has broad translational implications for microbe-associated GI neoplasia. Importantly, bile acid sequestration robustly attenuated the combined effects of H. pylori infection and iron depletion on gastric inflammation and cancer.
Authors
Madeline Alizadeh, Jean-Pierre Raufman
Abstract
Myotonic dystrophy type 1 (DM1) is a multisystem trinucleotide repeat expansion disorder characterized by the misregulated alternative splicing of critical mRNAs. Previous work in a transgenic mouse model indicated that aerobic exercise effectively improves splicing regulation and function in skeletal muscle. In this issue of the JCI, Mikhail et al. describe the safety and benefits of applying this approach in individuals affected by DM1. A 12-week aerobic exercise program improved aerobic capacity and mobility, but not by the mechanism observed in transgenic mice. Here, we consider the possible reasons for this disparity and review other salient findings of the study in the context of evolving DM1 research.
Authors
Samuel J. Mackenzie, Johanna Hamel, Charles A. Thornton
No posts were found with this tag.
Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)