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However, there is not a complete understanding of the factors that influence responsiveness to programmed death-ligand 1 (PD-L1) blockade. In particular, it is currently unclear whether the efficacy of PD-L1 blockade is dependent on the stage of disease. In a model of chronic lymphocytic choriomeningitis virus infection in mice, we show that exhausted CD8 T cells during the late stage of infection are refractory to rescue by PD-L1 blockade. Interestingly, PD-L1 blockade during the late stage of infection resulted in a biased expansion of PD-1+ CTLA-4+ regulatory T cells (Tregs) over antiviral CD8 T cells. Although previous studies have shown that Treg ablation can enhance the immune rescue by PD-L1 blockade, this regimen may induce lethal autoimmunity. In this report, we show that PD-L1 blockade together with CD4 T cell depletion effectively rescued deeply exhausted CD8 T cells and enhanced antiviral control during the late stage of chronic infection without any associated mortality. These data demonstrate the pleiotropic effects of anti\u2013PD-L1 therapy on both virus-specific CD8 T cells and Tregs, and suggest a novel strategy for effectively rescuing deeply exhausted CD8 T cells.<\/jats:p>","DOI":"10.4049\/jimmunol.1403237","type":"journal-article","created":{"date-parts":[[2015,6,27]],"date-time":"2015-06-27T12:26:16Z","timestamp":1435407976000},"page":"1054-1063","source":"Crossref","is-referenced-by-count":34,"title":["CD4 T Cell Depletion Substantially Augments the Rescue Potential of PD-L1 Blockade for Deeply Exhausted CD8 T Cells"],"prefix":"10.1093","volume":"195","author":[{"given":"Pablo","family":"Penaloza-MacMaster","sequence":"first","affiliation":[{"name":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center , Boston, MA 02215"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas M","family":"Provine","sequence":"additional","affiliation":[{"name":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center , Boston, MA 02215"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eryn","family":"Blass","sequence":"additional","affiliation":[{"name":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center , Boston, MA 02215"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan H","family":"Barouch","sequence":"additional","affiliation":[{"name":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center , Boston, MA 02215"},{"name":"Ragon Institute of MGH, MIT and Harvard , Boston, MA 02114"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2015,8,1]]},"reference":[{"key":"2025030703591526500_r1","doi-asserted-by":"crossref","first-page":"4911","DOI":"10.1128\/JVI.77.8.4911-4927.2003","article-title":"Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment","volume":"77","author":"Wherry","year":"2003","journal-title":"J. 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