title: Selective CD28 Antagonist Blunts Memory Immune Responses and Promotes Long-Term Control of Skin Inflammation in Nonhuman Primates.
abstract: Novel therapies that specifically target activation and expansion of pathogenic immune cell subsets responsible for autoimmune attacks are needed to confer long-term remission. Pathogenic cells in autoimmunity include memory T lymphocytes that are long-lived and present rapid recall effector functions with reduced activation requirements. Whereas the CD28 costimulation pathway predominantly controls priming of naive T cells and hence generation of adaptive memory cells, the roles of CD28 costimulation on established memory T lymphocytes and the recall of memory responses remain controversial. In contrast to CD80/86 antagonists (CTLA4-Ig), selective CD28 antagonists blunt T cell costimulation while sparing CTLA-4 and PD-L1-dependent coinhibitory signals. Using a new selective CD28 antagonist, we showed that Ag-specific reactivation of human memory T lymphocytes was prevented. Selective CD28 blockade controlled both cellular and humoral memory recall in nonhuman primates and induced long-term Ag-specific unresponsiveness in a memory T cell-mediated inflammatory skin model. No modification of memory T lymphocytes subsets or numbers was observed in the periphery, and importantly no significant reactivation of quiescent viruses was noticed. These findings indicate that pathogenic memory T cell responses are controlled by both CD28 and CTLA-4/PD-L1 cosignals in vivo and that selectively targeting CD28 would help to promote remission of autoimmune diseases and control chronic inflammation.
authors.affiliation: INSERM UMR 1064, Institut de Transplantation Urologie Néphrologie, Université de Nantes, 44000 Nantes, France; Effimune, 44000 Nantes, France;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Poirier
authors.affiliation: INSERM UMR 1064, Institut de Transplantation Urologie Néphrologie, Université de Nantes, 44000 Nantes, France; Centre Hospitalier Universitaire, 44000 Nantes, France; and.
authors.forename: Melanie
authors.identifier: http://orcid.org/0000-0002-8735-9723
authors.initials: M
authors.lastname: Chevalier
authors.affiliation: INSERM UMR 1064, Institut de Transplantation Urologie Néphrologie, Université de Nantes, 44000 Nantes, France; Effimune, 44000 Nantes, France;
authors.forename: Caroline
authors.initials: C
authors.lastname: Mary
authors.affiliation: INSERM UMR 1064, Institut de Transplantation Urologie Néphrologie, Université de Nantes, 44000 Nantes, France;
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hervouet
authors.affiliation: INSERM UMR 1064, Institut de Transplantation Urologie Néphrologie, Université de Nantes, 44000 Nantes, France;
authors.forename: David
authors.initials: D
authors.lastname: Minault
authors.affiliation: Department of Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Baker
authors.affiliation: INSERM UMR 1064, Institut de Transplantation Urologie Néphrologie, Université de Nantes, 44000 Nantes, France;
authors.forename: Simon
authors.identifier: http://orcid.org/0000-0001-8838-7091
authors.initials: S
authors.lastname: Ville
authors.affiliation: INSERM UMR 1064, Institut de Transplantation Urologie Néphrologie, Université de Nantes, 44000 Nantes, France; Centre Hospitalier Universitaire, 44000 Nantes, France; and.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Le Bas-Bernardet
authors.affiliation: INSERM UMR 1064, Institut de Transplantation Urologie Néphrologie, Université de Nantes, 44000 Nantes, France; Effimune, 44000 Nantes, France;
authors.forename: Nahzli
authors.identifier: http://orcid.org/0000-0002-3375-2773
authors.initials: N
authors.lastname: Dilek
authors.affiliation: INSERM UMR 1064, Institut de Transplantation Urologie Néphrologie, Université de Nantes, 44000 Nantes, France; Effimune, 44000 Nantes, France;
authors.forename: Lyssia
authors.initials: L
authors.lastname: Belarif
authors.affiliation: Centre Hospitalier Universitaire, 44000 Nantes, France; and.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Cassagnau
authors.affiliation: Department of Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom.
authors.forename: Linda
authors.initials: L
authors.lastname: Scobie
authors.affiliation: INSERM UMR 1064, Institut de Transplantation Urologie Néphrologie, Université de Nantes, 44000 Nantes, France; Centre Hospitalier Universitaire, 44000 Nantes, France; and.
authors.forename: Gilles
authors.initials: G
authors.lastname: Blancho
authors.affiliation: INSERM UMR 1064, Institut de Transplantation Urologie Néphrologie, Université de Nantes, 44000 Nantes, France; Effimune, 44000 Nantes, France; bernard.vanhove@univ-nantes.fr.
authors.forename: Bernard
authors.initials: B
authors.lastname: Vanhove
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D060890:B7-H1 Antigen / Q000276:immunology; D018106:CD28 Antigens / Q000037:antagonists & inhibitors* / Q000276:immunology; D060908:CTLA-4 Antigen / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D048530:Papio anubis; D015398:Signal Transduction / Q000276:immunology; D012867:Skin / Q000276:immunology* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014775:Virus Activation / Q000276:immunology
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D018106:CD28 Antigens; D060908:CTLA-4 Antigen