The T cell receptor (TCR) repertoire is diverse, thus allowing recognition of a wide range of pathogens by T cells. In humans, the study of the formation of TCR repertoires is problematic because of the difficulty in performing investigations in vivo. In this issue of the JCI, Khosravi-Maharlooei and colleagues describe a new humanized mouse model that allows direct investigations on this topic. Using high-throughput and single-cell TCR–complementarity-determining region 3 β (TCR-CDR3β) sequencing, the authors were able to demonstrate that human thymic selection is a major driver of TCR sequence sharing, also implicating a preferential selection of shared cross-reactive CDR3βs during repertoire formation.
Antonio La Cava
For high-risk and refractory hematological malignancies, allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only available curative therapy, with benefits derived from the antigenic disparity between recipient cancer and the incoming immune system. This immunologic mismatch can also lead to lethal graft-versus-host disease (GVHD), and immunosuppression strategies, including high-dose posttransplantation cyclophosphamide (PTCy), have been developed to allow for safe alloHSCT delivery. In this issue of JCI, Wachsmuth et al. present the results of preclinical studies designed to evaluate the mechanisms that underlie efficacy of PTCy after alloHSCT. The results of this study challenge previous reports indicating that alloreactive T cell elimination and thymic clonal deletion are primary mediators of PTCy efficacy and provide strong evidence to support FoxP3+CD4+ Tregs as important effectors of PTCy benefits.
Vedran Radojcic, Leo Luznik
African Americans are at increased risk of cancer and associated mortalities compared with European American populations. Socioeconomic, cultural, and biological factors have been implicated in this discrepancy. In this issue of the JCI, Piyarathna et al. identify a set of genes that are upregulated in a number of tumor types in African American cancer patients as compared with European American patients. These genes were associated with enhanced oxidative phosphorylation and upregulation of transcription factors that promote mitochondrial biogenesis, resulting in greater numbers of mitochondria in tumor samples from African American subjects. Together, these results indicate that mitochondria dysfunction may underlie the increased cancer incidence and poor outcomes observed in African American patients.
Jennifer L. Beebe-Dimmer, Kathleen A. Cooney
Acute kidney injury (AKI) is one of the most important risk factors for chronic and progressive kidney disease, leading to end-stage kidney failure. Tubule epithelial regeneration leads to the resolution of renal failure in AKI. Failure of tubule epithelial regeneration leads to concomitant hypoxia from loss of microcirculation, which serves as a critical factor leading to chronic kidney disease. In this issue of the JCI, Li et al. show that hypoxia activates the stress-responsive transcription factor FoxO3. Increased FoxO3 protein abundance leads to alterations in tubular epithelial autophagy and metabolism, highlighting an important mechanism causing permanent renal damage even after an acute injury.
Xiangchen Gu, Archana Raman, Katalin Susztak
Vertical sleeve gastrectomy (VSG) is an effective therapeutic approach for obesity and type 2 diabetes but is associated with osteoporosis. In this issue of the JCI, Li et al. report that VSG rapidly reduces bone mass, as observed in humans, via rapid demineralization and decreased bone formation, independent of weight loss or Ca2+/vitamin D deficiency. VSG also reduces bone marrow adipose tissue, in part via increased granulocyte–colony stimulating factor (G-CSF). The interplay between VSG-mediated effects on systemic metabolism and bone biology remain to be investigated. These findings suggest novel mechanisms and therapeutic targets for bariatric surgery–induced osteoporosis.
Soravis Osataphan, Mary Elizabeth Patti
Glucocorticoids (GCs) are essential for proper glycemic control, but in excess, can lead to hyperglycemia and diabetes. In this issue of the JCI, Cui et al. elucidate a mechanism by which GCs regulate gluconeogenesis utilizing the transcription factor Krüppel-like factor 9 (KLF9) in physiology and disease settings. They report that KLF9 is a GC-inducible factor that ultimately increases the transcription of proliferator-activated receptor γ coactivator 1 α (PGC1α), resulting in gluconeogenesis. Given the high incidence of GC-induced diabetes, identification of this signaling axis provides, not only critical scientific insight, but also a foundation for preventative therapies for patients receiving chronic GC treatment.
David R. Sweet, Liyan Fan, Mukesh K. Jain
Chimeric antigen receptor (CAR) T cells have been shown to successfully treat some hematopoietic malignancies. Recognition of a relevant target on malignant cells and the proper costimulatory molecule are essential for CAR T cell efficacy. In this issue of the JCI, Cohen et al. conducted an early phase trial to evaluate B cell maturation antigen–targeting (BCMA-targeting) CAR T cells in patients with refractory multiple myeloma. Patients who received the highest dose of BCMA-targeting CAR T cells in combination with lymphodepletion had the greatest response. The results of the study provide further support for the use of BCMA-targeting CAR T cells for myeloma, and reiterate the importance of space and cell dose for CAR T cell success.
Ivan Borrello, Philip H. Imus
White adipose tissue (WAT) dysfunction is generally thought to promote the development of alcoholic liver disease (ALD) in alcoholics by releasing free fatty acids and inflammatory mediators. This explains, at least in part, the synergistic or additive effects of alcohol and obesity on liver disease progression. In this issue of the JCI, Shen et al. establish a previously unrecognized concept that brain alcohol sensing enhances thermogenesis of brown adipose tissue (BAT) through sympathetic nerve activation. BAT functions as hepatoprotective machinery to counteract the development of ALD, implying a therapeutic potential of BAT activity modulation for the treatment of ALD.
Seonghwan Hwang, Bin Gao
Chimeric antigen receptor (CAR) T cells are an effective therapy for relapsed or refractory pediatric B cell leukemia. Analysis of the starting material, the T cells collected from the patient prior to CAR manufacture, reveals possible biomarkers of cells destined to perform poorly in patients. Long-term follow-up shows that long periods of B cell aplasia, a marker of in vivo CAR activity, are associated with longer remission but also a higher chance of antigen-negative relapse. The role of transplantation as consolidative therapy is unclear in this nonrandomized data, but clearly warrants further study.
David M. Barrett
The Epstein-Barr virus (EBV) is estimated to infect a large part of the population and is associated with a variety of human tumors; therefore, EBV is an important target for vaccine development. In this issue of the JCI, Rühl et al. developed a promising heterologous prime-boost vaccination strategy for EBV-associated malignancies and symptomatic primary infection. The authors show that two prime-boost regimens, using either dendritic cells or an adenovirus approach targeting nuclear antigen EBNA1 followed by a modified vaccinia virus Ankara (MVA) booster, induced significant T cell–mediated, EBV-specific immune control and Ab production. These findings suggest that administration of heterologous prime-boost vaccinations targeting EBNA1 may result in potent CD4+ and CD8+ T cell–mediated EBV immune control and may be a promising clinical approach.
Sandhya Sharma, Rayne H. Rouce
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