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In contrast, in scenarios of persistent antigen stimulation, such as chronic infections and cancer, antigen-specific CTLs show a gradual decrease in effector function, a phenomenon that has been termed CD8+ T cell \u201cexhaustion\u201d or \u201cdysfunction.\u201d Another hyporesponsive state, termed \u201canergy\u201d, is observed when T cells are activated in the absence of positive costimulatory signals. Among the many negative regulators induced in hyporesponsive T cells are inhibitory cell\u2013surface receptors, such as PD-1, LAG-3, CTLA-4, and TIM-3; \u201ccheckpoint blockade\u201d therapies that involve treatment of patients with cancer with blocking antibodies to those receptors show considerable promise in the clinic because the blocking antibodies can mitigate hyporesponsiveness and promote tumor rejection. In this review, we describe recent advances in our molecular understanding of these hyporesponsive states. We review evidence for the involvement of diverse transcription factors, metabolic programs, and chromatin accessibility changes in hyporesponsive T cells, and we discuss how checkpoint blockade therapies affect the molecular program of CD8+ T cell exhaustion.<\/jats:p>","DOI":"10.1189\/jlb.2ri0317-097r","type":"journal-article","created":{"date-parts":[[2017,6,13]],"date-time":"2017-06-13T00:30:15Z","timestamp":1497313815000},"page":"601-615","source":"Crossref","is-referenced-by-count":40,"title":["Transcriptional and epigenetic regulation of T cell hyporesponsiveness"],"prefix":"10.1093","volume":"102","author":[{"given":"Renata M","family":"Pereira","sequence":"first","affiliation":[{"name":"Instituto de Microbiologia Paulo de G\u00f3es, Universidade Federal do Rio de Janeiro , Rio de Janeiro, Brazil"}]},{"given":"Patrick G","family":"Hogan","sequence":"additional","affiliation":[{"name":"Division of Signaling and Gene Expression, La Jolla Institute , San Diego, California, USA"}]},{"given":"Anjana","family":"Rao","sequence":"additional","affiliation":[{"name":"Division of Signaling and Gene Expression, La Jolla Institute , San Diego, California, USA"},{"name":"Sanford Consortium for Regenerative Medicine , La Jolla, California, USA"},{"name":"Department of Pharmacology and Moores Cancer Center, University of California , San Diego, La Jolla, California, USA"}]},{"given":"Gustavo J","family":"Martinez","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, Chicago Medical School , North Chicago, Illinois, USA"}]}],"member":"286","published-online":{"date-parts":[[2017,6,12]]},"reference":[{"key":"2023013012233892700_B1","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/nri3307","article-title":"Transcriptional control of effector and memory CD8+ T cell differentiation","volume":"12","author":"Kaech","year":"2012","journal-title":"Nat. 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