title: The role of CD4+ T cell help and CD40 ligand in the in vitro expansion of HIV-1-specific memory cytotoxic CD8+ T cell responses.
abstract: CD4(+) T cells have been shown to play a critical role in the maintenance of an effective anti-viral CD8(+) CTL response in murine models. Recent studies have demonstrated that CD4(+) T cells provide help to CTLs through ligation of the CD40 receptor on dendritic cells. The role of CD4(+) T cell help in the expansion of virus-specific CD8(+) memory T cell responses was examined in normal volunteers recently vaccinated to influenza and in HIV-1 infected individuals. In recently vaccinated normal volunteers, CD4(+) T cell help was required for optimal in vitro expansion of influenza-specific CTL responses. Also, CD40 ligand trimer (CD40LT) enhanced CTL responses and was able to completely substitute for CD4(+) T cell help in PBMCs from normal volunteers. In HIV-1 infection, CD4(+) T cell help was required for optimal expansion of HIV-1-specific memory CTL in vitro in 9 of 10 patients. CD40LT could enhance CTL in the absence of CD4(+) T cell help in the majority of patients; however, the degree of enhancement of CTL responses was variable such that, in some patients, CD40LT could not completely substitute for CD4(+) T cell help. In those HIV-1-infected patients who demonstrated poor responses to CD40LT, a dysfunction in circulating CD8(+) memory T cells was demonstrated, which was reversed by the addition of cytokines including IL-2. Finally, it was demonstrated that IL-15 produced by CD40LT-stimulated dendritic cells may be an additional mechanism by which CD40LT induces the expansion of memory CTL in CD4(+) T cell-depleted conditions, where IL-2 is lacking.
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. m.ostrowski@utoronto.ca
authors.forename: M A
authors.initials: MA
authors.lastname: Ostrowski
authors.forename: S J
authors.initials: SJ
authors.lastname: Justement
authors.forename: L
authors.initials: L
authors.lastname: Ehler
authors.forename: S B
authors.initials: SB
authors.lastname: Mizell
authors.forename: S
authors.initials: S
authors.lastname: Lui
authors.forename: J
authors.initials: J
authors.lastname: Mican
authors.forename: B D
authors.initials: BD
authors.lastname: Walker
authors.forename: E K
authors.initials: EK
authors.lastname: Thomas
authors.forename: R
authors.initials: R
authors.lastname: Seder
authors.forename: A S
authors.initials: AS
authors.lastname: Fauci
mesh_terms: D000276:Adjuvants, Immunologic / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D023201:CD40 Ligand / Q000502:physiology*; D002450:Cell Communication / Q000276:immunology; D002469:Cell Separation; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D009980:Influenza A virus / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008211:Lymphocyte Cooperation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000821:virology
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D023201:CD40 Ligand