title: Quiescence of Memory CD8(+) T Cells Is Mediated by Regulatory T Cells through Inhibitory Receptor CTLA-4.
abstract: Immune memory cells are poised to rapidly expand and elaborate effector functions upon reinfection yet exist in a functionally quiescent state. The paradigm is that memory T cells remain inactive due to lack of T cell receptor (TCR) stimuli. Here, we report that regulatory T (Treg) cells orchestrate memory T cell quiescence by suppressing effector and proliferation programs through inhibitory receptor, cytotoxic-T-lymphocyte-associated protein-4 (CTLA-4). Loss of Treg cells resulted in activation of genome-wide transcriptional programs characteristic of effector T cells and drove transitioning as well as established memory CD8(+) T cells toward terminally differentiated KLRG-1(hi)IL-7Rα(lo)GzmB(hi) phenotype, with compromised metabolic fitness, longevity, polyfunctionality, and protective efficacy. CTLA-4 functionally replaced Treg cells in trans to rescue memory T cell defects and restore homeostasis. These studies present the CTLA-4-CD28-CD80/CD86 axis as a potential target to accelerate vaccine-induced immunity and improve T cell memory quality in current cancer immunotherapies proposing transient Treg cell ablation.
authors.affiliation: The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Vandana
authors.initials: V
authors.lastname: Kalia
authors.affiliation: The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Laura Anne
authors.initials: LA
authors.lastname: Penny
authors.affiliation: The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Yevgeniy
authors.initials: Y
authors.lastname: Yuzefpolskiy
authors.affiliation: The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Florian Martin
authors.initials: FM
authors.lastname: Baumann
authors.affiliation: The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA. Electronic address: sarkarkalia@gmail.com.
authors.forename: Surojit
authors.initials: S
authors.lastname: Sarkar
mesh_terms: D000069594:Abatacept; D000818:Animals; D060887:B7 Antigens / Q000378:metabolism; D018106:CD28 Antigens / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000378:metabolism*; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D053804:Granzymes / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D018796:Immunoconjugates / Q000008:administration & dosage; D007156:Immunologic Memory / Q000187:drug effects / Q000235:genetics; D037181:Lectins, C-Type; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D011971:Receptors, Immunologic / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D060887:B7 Antigens; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018796:Immunoconjugates; C451496:Klrg1 protein, mouse; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; D000069594:Abatacept; D053804:Granzymes; C509214:Gzmb protein, mouse