Etienne Humblin, Isabel Korpas, Nataliya Prokhnevska, Abishek Vaidya, Dan Filipescu, Jiahua Lu, Verena van der Heide, Carlos Alberto de Carvalho Fraga, Tesia Bobrowski, Adam Marks, Matthew D. Park, Helder I. Nakaya, Emily Bernstein, Brian D. Brown, Amaia Lujambio, David Dominguez-Sola, Brad R. Rosenberg, Alice O. Kamphorst
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引用次数: 0
Abstract
During persistent antigen stimulation, CD8+ T cell responses are maintained by progenitor exhausted CD8+ T (Tpex) cells. Tpex cells respond to blockade of the inhibitory receptor programmed cell death-1 (PD-1), and regulation of their differentiation is critical for immunotherapies. Tpex cells highly express inducible costimulator (ICOS), but how ICOS modulates PD-1+CD8+ T cells is not clear. During chronic infection, intrinsic ICOS deficiency increased number and quality of virus-specific CD8+ T cells. Loss of ICOS potentiated activity of the transcription factor forkhead box O1 (FoxO1) and memory-like features of Tpex cells. ICOS-deficient Tpex cells were poised to generate effecor-like cells with improved survival and cytokine production. ICOS-ligand (ICOSL) blockade expanded effector-like PD-1+CD8+ T cells, reduced viral load, and improved response to PD-1 blockade. Similarly, in a mouse model of hepatocellular carcinoma, ICOS inhibition enhanced tumor-specific CD8+ T cell responses and tumor control by PD-1 blockade. Overall, we show that sustained ICOS costimulation limits CD8+ T cell responses during chronic antigen exposure.
期刊介绍:
Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.