title: Tight regulation of memory CD8(+) T cells limits their effectiveness during sustained high viral load.
abstract: To design successful vaccines for chronic diseases, an understanding of memory CD8(+) T cell responses to persistent antigen restimulation is critical. However, most studies comparing memory and naive cell responses have been performed only in rapidly cleared acute infections. Herein, by comparing the responses of memory and naive CD8(+) T cells to acute and chronic lymphocytic choriomeningitis virus infection, we show that memory cells dominated over naive cells and were protective when present in sufficient numbers to quickly reduce infection. In contrast, when infection was not rapidly reduced, because of high antigen load or persistence, memory cells were quickly lost, unlike naive cells. This loss of memory cells was due to a block in sustaining cell proliferation, selective regulation by the inhibitory receptor 2B4, and increased reliance on CD4(+) T cell help. Thus, emphasizing the importance of designing vaccines that elicit effective CD4(+) T cell help and rapidly control infection.
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Erin E
authors.initials: EE
authors.lastname: West
authors.forename: Ben
authors.initials: B
authors.lastname: Youngblood
authors.forename: Wendy G
authors.initials: WG
authors.lastname: Tan
authors.forename: Hyun-Tak
authors.initials: HT
authors.lastname: Jin
authors.forename: Koichi
authors.initials: K
authors.lastname: Araki
authors.forename: Gabriela
authors.initials: G
authors.lastname: Alexe
authors.forename: Bogumila T
authors.initials: BT
authors.lastname: Konieczny
authors.forename: Silvia
authors.initials: S
authors.lastname: Calpe
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Cox
authors.initials: C
authors.lastname: Terhorst
authors.forename: W Nicholas
authors.initials: WN
authors.lastname: Haining
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
mesh_terms: D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D001117:Arenaviridae Infections / Q000276:immunology* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002908:Chronic Disease; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D007156:Immunologic Memory; D008217:Lymphocytic choriomeningitis virus / Q000472:pathogenicity / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019899:Paracrine Communication; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism*; D000071176:Signaling Lymphocytic Activation Molecule Family; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D019562:Viral Load; D014765:Viral Vaccines
chemical_list: D015703:Antigens, CD; C490007:Cd244a protein, mouse; D016207:Cytokines; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family; D014765:Viral Vaccines