title: Influenza-induced, helper-independent CD8+ T cell responses use CD40 costimulation at the late phase of the primary response.
abstract: The helper-dependent pathway of priming CD8(+) T cells involves "licensing" of DCs by CD40L on CD4(+) T cells. The helper-independent ("helpless") pathways elicited by many viruses, including influenza, are less widely understood. We have postulated that CD40L can be up-regulated on DCs by such viruses, and this promotes priming of CD8(+) T cells via CD40. Most studies on costimulation have been performed in the presence of CD4(+) T cells, and so the role of CD40L costimulation under helpless circumstances has not been fully elucidated. Here, we investigated such a role for CD40L using CD40L KO mice. Although the number of influenza-specific CD8(+) T cells was unaffected by the absence of CD4(+) T cells, it was markedly decreased in the absence of CD40L. Proliferation (the number of CD44(+)BrdU(+) influenza-specific CD8(+) T cells) in the primary response was diminished in CD40L KO mice at Day 8 but not at Day 5 after infection. MLR studies indicated that CD40L expression on DCs was critical for CD8(+) T cell activation. Adoptive transfer of CD40 KO CD8(+) T cells compared with WT cells confirmed that CD40 on such cells was critical for the generation of primary anti-influenza CD8(+) T cell responses. The late effect also corresponded with the late expression of CD40 by influenza-specific CD8(+) T cells. We suggest that costimulation via CD40L on DCs and CD40 on CD8(+) T cells is important in optimizing primary CD8(+) T cell responses during influenza infection.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3052, Australia.
authors.forename: Shirley G K
authors.initials: SG
authors.lastname: Seah
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Brady
authors.forename: Emma M
authors.initials: EM
authors.lastname: Carrington
authors.forename: Wy Ching
authors.initials: WC
authors.lastname: Ng
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: Andrew M
authors.initials: AM
authors.lastname: Lew
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhan
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D061025:Costimulatory and Inhibitory T-Cell Receptors / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D009980:Influenza A virus; D008213:Lymphocyte Activation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000378:metabolism
chemical_list: D019013:CD40 Antigens; D061025:Costimulatory and Inhibitory T-Cell Receptors; D023201:CD40 Ligand