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Effective vaccines against intracellular pathogens rely on the generation and maintenance of memory CD8 T cells (T(mem)). Hitherto, evidence has indicated that CD8 T(mem) use the common γ-chain cytokine IL-15 for their steady-state maintenance in the absence of Ag. This evidence, however, has been amassed predominantly from models of acute, systemic infections. Given that the route of infection can have significant impact on the quantity and quality of the resultant T(mem), reliance on limited models of infection may restrict our understanding of long-term CD8 T(mem) survival. In this article, we show IL-15-independent generation, maintenance, and function of CD8 T(mem) after respiratory infection with influenza virus. Importantly, we demonstrate that alternating between mucosal and systemic deliveries of the identical virus prompts this change in IL-15 dependence, necessitating a re-evaluation of the current model of CD8 T(mem) maintenance.
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http://dx.doi.org/10.4049/jimmunol.1004022 | DOI Listing |
Immunity
July 2025
Marc and Jennifer Lipschultz Precision Immunology Institute, Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, USA; Diabetes, Obesity and Metabolism Institute, Department of Medicine, ISMMS, New York, NY 10029, USA. Electronic address: d
Generation of functional memory CD8 T cells typically requires engagement of CD4 T cells. In certain acutely resolving infections, however, effector and memory CD8 T (Tmem) cell formation appears impervious to the lack of CD4 T cell help. Nevertheless, "helpless" CD8 Tmem cells may respond poorly upon rechallenge.
View Article and Find Full Text PDFSci Rep
May 2025
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
Exhausted CD8 T cells (T) arising during chronic infections and cancer have reduced functional capacity and limited fate flexibility that prevents optimal disease control and response to immunotherapies. Compared to memory (T) cells, T have a unique open chromatin landscape underlying a distinct gene expression program. How T transcriptional and epigenetic landscapes are regulated through histone post-translational modifications (hPTMs) remains unclear.
View Article and Find Full Text PDFLiver Int
April 2025
Department of Clinical and Translational Research Center, Affiliated Hospital of Nantong University & Medical School of Nantong University, Nantong, China.
Background: Transmembrane (TMEM) proteins are involved in fundamental biological processes such as material transport and signal transduction. TMEM115 is a member of the TMEM protein family, but its significance in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigate the clinical predictive significance and potential functions of TMEM115 in HCC.
View Article and Find Full Text PDFAlthough the CXCL12/CXCR4 pathway has been prior investigated for its prometastatic and immuno- suppressive roles in the tumor microenvironment, evidence on the spatiotemporal regulation of these hallmarks has been lacking. Here, we demonstrate that CXCL12 forms a gradient specifically around cancer cell intravasation doorways, also known as Tumor Microenvironment of Metastasis (TMEM) doorways, thus facilitating the chemotactic translocation of prometastatic tumor cells expressing CXCR4 toward the perivascular TMEM doorways for subsequent entry into peripheral circulation. Fur- thermore, we demonstrate that the CXCL12-rich micro-environment around TMEM doorways may cre- ate immunosuppressive niches, whereby CD8 T cells, despite being attracted to these regions, often exhibit reduced effector functions, limiting their efficacy.
View Article and Find Full Text PDFBiochem Biophys Rep
September 2024
Scleroderma Genomics and Health Disparities Unit, NIAMS, NIH, Bethesda, USA.
Mesenchymal stromal cells (MSCs) have evolved as an invaluable therapeutic cell type due to their broad therapeutic properties. Bone marrow-derived MSCs are currently being applied in numerous clinical trials, and the initial results have been encouraging. However, heterogeneous responsiveness amongst patients is also being experienced; therefore, the efficacy of MSCs is still debatable.
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