title: Unlike CD4+ T-cell help, CD28 costimulation is necessary for effective primary CD8+ T-cell influenza-specific immunity.
abstract: The importance of costimulation on CD4(+)  T cells has been well documented. However, primary CTLs against many infections including influenza can be generated in the absence of CD4(+)  T-cell help. The role of costimulation under such "helpless" circumstances is not fully elucidated. Here, we investigated such a role for CD28 using CTLA4Ig transgenic (Tg) mice. To ensure valid comparison across the genotypes, we showed that all mice had similar naïve precursor frequencies and similar peak viral loads. In the absence of help, viral clearance was significantly reduced in CTLA4Ig Tg mice compared with WT mice. CD44(+) BrdU(+) influenza-specific CD8(+)  T cells were diminished in CTLA4Ig Tg mice at days 5 and 8 postinfection. Adoptive transfer of ovalbumin-specific transgenic CD8(+)  T cells (OT-I)-I cells into WT or CTLA4Ig Tg mice revealed that loss of CD28 costimulation resulted in impairment in OT-I cell division. As shown previously, neither viral clearance nor the generation of influenza-specific CD8(+)  T cells was affected by the absence of CD4(+)  T cells alone. In contrast, both were markedly impaired by CD28 blockade of "helpless" CD8(+)  T cells. We suggest that direct CD28 costimulation of CD8(+)  T cells is more critical in their priming during primary influenza infection than previously appreciated.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Australia.
authors.forename: Shirley G K
authors.initials: SG
authors.lastname: Seah
authors.forename: Emma M
authors.initials: EM
authors.lastname: Carrington
authors.forename: Wy C
authors.initials: WC
authors.lastname: Ng
authors.forename: Gabrielle T
authors.initials: GT
authors.lastname: Belz
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Brady
authors.forename: Robyn M
authors.initials: RM
authors.lastname: Sutherland
authors.forename: Manuela S
authors.initials: MS
authors.lastname: Hancock
authors.forename: Nicole L
authors.initials: NL
authors.lastname: La Gruta
authors.forename: Lorena E
authors.initials: LE
authors.lastname: Brown
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Turner
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhan
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lew
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D005434:Flow Cytometry; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000821:virology; D013047:Specific Pathogen-Free Organisms; D018709:Statistics, Nonparametric; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse